From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology
Open accessAbstract
The continued drug discovery failures in complex neurodegenerative diseases, including Alzheimer's disease (AD), has raised questions about the classical paradigm “one‐drug, one‐target, one‐disease.” In parallel, the ever‐increasing awareness of the multiplicity of the underlying pathways has led to the affirmation of polypharmacological approaches. Polypharmacology, which broadly embodies the use of pharmaceutical agents acting on multiple targets, seems to be the best way to restore the complex diseased network and to provide disease‐modifying effects in AD. In this review, our aim is to provide a roadmap into a world that is still only partly explored and that should be seen as a continuum of pharmacological opportunities, from drug combinations to multitarget‐directed ligands (both codrugs and hybrids). Each modality has unique features that can be effectively exploited by medicinal chemists. We argue that understanding their advantages and drawbacks is very helpful in choosing a proper approach and developing successful AD multitarget drug‐discovery endeavors. We also briefly dwell on (co)target validation, an aspect that is quite often neglected, but critical for an efficient clinical translation. We substantiate our discussion with instructive examples taken from the recent literature. Our wish is that, in spite of the specter of the high attrition rates, best researchers preferring to enter, stay, and progress in the field would help grow the sector and develop AD polypharmacology to full potential.
AI snapshot
Written from the paper’s full text.
TL;DR
This review argues that Alzheimer’s disease polypharmacology should be viewed as a continuum from drug combinations to multitarget-directed ligands (MTDLs), including codrugs and hybrids. It uses recent preclinical and clinical examples to show how target-pair validation and modality choice shape AD drug-discovery efforts.
Key findings
- Polypharmacology includes drug combinations (cocktails or fixed-dose combinations) and MTDLs (codrugs or hybrids); the FDA approved a fixed-dose combination of donepezil and memantine in 2014 for moderate-to-severe AD.
- Combination approaches have translated faster clinically than MTDLs; examples include cromolyn–ibuprofen in phase III (NCT02547818), quercetin–dasatinib in phase I (NCT04063124), mefloquine–donepezil/THN201 in phase I (NCT03698695), masitinib plus AChEIs in phase III (NCT01872598), and prolonged-release melatonin plus AChEIs with or without memantine.
- MTDL examples discussed include donecopride, memagal/ARN14140, CM-414, contilisant, quinoline–indole hybrid 42, tacrine–hCB2R hybrids, and tacrine–tryptophan hybrid 47; ladostigil was safe and well tolerated in a 3-year phase II trial (NCT01429623) but did not delay dementia progression.
- The paper proposes that validated target pairs should demonstrate additive or synergistic effects in reliable in vitro and in vivo models, and outlines a four-step validation process: selective chemical probes, cytotoxicity evaluation, cell-model synergy, and in vivo confirmation.
Methods
- Narrative review; no systematic review, meta-analysis, or primary experimental dataset is reported.
- Synthesizes recent literature examples of AD polypharmacology, focusing on drug combinations, codrugs, hybrids, and selected clinical trials.
- Discusses multitarget validation from a network-pharmacology perspective and proposes a sequential four-step validation flowchart.
Limitations
- The authors state that target validation is often neglected and rigorous network target validation is not always feasible, especially in academia; most MTDL papers report only in vitro activity, sometimes with inadequate investigation of multitarget mechanisms, and in vivo efficacy studies may be cost-prohibitive or ethically limited.
- The authors note no ongoing clinical trials involving codrugs for AD, and some clinical combinations reached trials without strong in vivo validation of synergy (e.g., masitinib plus AChEIs); GV-971’s mechanism remains unclear and controversial.
- Evident from the text: as a narrative review, it uses illustrative examples rather than exhaustive or systematic evidence synthesis, with no quantitative pooling or formal risk-of-bias assessment.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
0 of 103 cited sources checked · 0 supported · 0 flagged
- Findingcitation
In an in vivo AD mouse model, the cromolyn-ibuprofen combination showed better effects than cromolyn or ibuprofen alone.
“An efficacy study in in vivo AD mouse model evidenced better effects of the drug combination compared with cromolyn and ibuprofen alone.59”
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- Findingreasoning
Clinical trial results have shown amelioration of disease progression in patients treated with prolonged-release melatonin compared with placebo.
“According to what was observed in preclinical studies, clinical trial results have underlined an amelioration of disease progression in patients treated with PRM compared with placebo.”
Quote in the paperSubstantial claim - Findingcitation
Early results of the THN201 clinical trial revealed an extension of the pharmacological profile of THN201 compared with donepezil monotherapy in healthy male volunteers after scopolamine challenge.
“The early results of this clinical trial 71 revealed an extension of the pharmacological profile of THN201 compared with donepezil monotherapy in healthy male volunteers, after impairment by a scopolamine challenge.”
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- Findingcitation
In vitro assays showed better free radical-scavenging properties for ibuprofen-lipoic acid codrugs 13-15 than for ibuprofen and lipoic acid tested alone.
“Moreover, in vitro assays showed better free radical-scavenging properties for 13 to 15 than 4 and 12 tested alone.85”
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- Findingcitation
In a microsomal incubation assay with human liver microsomes, codrug 20 was rapidly cleaved by cellular unspecific esterases and widely metabolized to silybin-glycosides (21) and tacrine hemisuccinamide (22).
“The experiment showed, by microsomal incubation assay with human liver microsomes that 20 was rapidly cleaved by cellular unspecific esterases and widely metabolized to silybin-glycosides (21) and tacrine hemisuccinamide (22).”
Quote in the paperSubstantial claim
- Findingcitation
In an in vivo rat model, the positive in vitro results for compound 13 were confirmed.
“The most promising compound 13 was then investigated in in vivo rat model, where the positive in vitro results were confirmed.85”
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- Findingcitation
In a rat model of AD following Aβ40 peptide injection, treatment with codrug 13 reduced Aβ40 peptide accumulation in cerebral cortex more significantly than treatment with ibuprofen or lipoic acid alone.
“After treatment with codrug 13, Aβ40 peptide accumulation was reduced in cerebral cortex in a more significant way than after treatment with 4 or 12 alone.90”
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- Premisecitation
Available evidence that the advantages of fixed-dose combinations increase treatment adherence and persistence is contradictory.
“However, available evidence that these advantages would increase treatment adherence and persistence is contradictory.47”
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- Interpretationreasoning
After experimental evidence of additive or synergistic effects of two existing drugs in appropriate in vitro and in vivo models, the transition to clinical phases is faster for drug combinations than for MTDLs, which are new chemical entities.
“Indeed, after providing experimental evidence of the additive or synergistic effects of two existing drugs by appropriate in vitro and in vivo models, the transition to the clinical phases results faster compared with that needed for MTDLs, which are completely new chemical entities.”
Quote in the paperSubstantial claim - Premisecitation
Drug cocktails have the advantage of permitting adjustment of the dose regimen, allowing a personalized medicine approach.
“In addition, drug cocktails have the considerable advantage of permitting to adjust the dose regimen, thus allowing a personalized medicine approach.48”
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- Interpretationreasoning
Polypharmacological approaches based on drug combinations have proven more successful in clinical translation than MTDLs.
“From a drug discovery perspective, polypharmacological approaches based on drug combinations have proven more successful in terms of clinical translation with respect to MTDLs.”
Quote in the paperSubstantial claim - Premisecitation
The AD sector has experienced high attrition rates.
“However, there hangs the specter of the high attrition rates experienced by the AD sector.17”
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- Interpretationreasoning
Modulating more than one molecular target (a polypharmacological approach) is an effective way to attack multifactorial neurodegenerative diseases.
“This creates a simple but indisputable background to the idea of effectively attacking them through the modulation of more than one molecular target, that is, a polypharmacological approach.4”
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- Premisenone given
Combinations show an inherently higher risk of drug-drug interactions and toxic effects.
“On the other side, combinations show an inherently higher risk of drug-drug interactions (DDIs) and of toxic effects.”
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Simultaneous modulation of multiple targets by one or more chemical entities is correlated with lower doses usage.
“Additionally, the simultaneous modulation of multiple targets by one or more chemical entities is correlated to the concept of lower doses usage.8”
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- Premisenone given
To date, there is a limited number of MTDLs whose development was preceded by drug combination studies and inspired by rigorous target validation studies.
“To date, there is a number, albeit limited, of MTDLs in which drug combination studies have preceded their development, and whose design has been inspired by rigorous target validation studies (vide infra).”
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In 2014, the FDA approved a fixed-dose combination of donepezil and memantine for the symptomatic treatment of moderate-to-severe AD.
“Notably, in 2014, the Food and Drug Administration (FDA) approved a fixed-dose combination of AChE inhibitor (AChEI) donepezil (1) and NMDAR blocker memantine (2) for the symptomatic treatment of moderate-to-severe AD (Figure 4).46”
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- Premisecitation
Adherence to a complex therapy is unlikely for forgetful AD patients and their caregivers.
“Both are critical issues in AD: (a) adherence to a complex therapy is unlikely for forgetful AD patients and their caregivers; (b) coexistence of chronic disease, polypharmacy, and impaired organ functions makes geriatric population particularly susceptible to DDIs.49”
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- Interpretationreasoning
The ineffectiveness of current AD drugs indicates the necessity of searching for new drugs by exploiting polypharmacological approaches.
“This is a clear indication of the necessity of searching for new drugs by exploiting polypharmacological approaches.”
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Neurodegenerative diseases, including Alzheimer's disease, are multifactorial, caused by multiple genetic, environmental, or endogenous factors, possibly operating simultaneously.
“A strong argument in favor of complex pharmacology strategies for the treatment of complex neurodegenerative diseases is based on the fact that these diseases are multifactorial, that is, they are caused by multiple factors, being possibly genetic, environmental, endogenous, or even having more than one factor operating at the same time.21”
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- Premisecitation
Experimental studies can effectively demonstrate networked mechanisms of action, synergistic or additive activity, and acceptable safety at clinically achievable drug concentrations.
“As an alternative to the in silico modeling, purposely addressed experimental studies can effectively demonstrate networked mechanisms of action, synergistic or additive activity, and acceptable safety at clinically achievable drug concentrations.45”
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- Premisecitation
Cell-based systems are a compromise between isolated proteins and in vivo screening, maintaining experimental efficiency while preserving critical molecular pathway interactions.
“From a polypharmacology perspective, the cell-based systems are a perfect compromise between isolated proteins and in vivo screening: they maintain a reasonable experimental efficiency while preserving critical molecular pathway interactions.3”
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- Premisecitation
Coexistence of chronic disease, polypharmacy, and impaired organ functions makes the geriatric population particularly susceptible to drug-drug interactions.
“Both are critical issues in AD: (a) adherence to a complex therapy is unlikely for forgetful AD patients and their caregivers; (b) coexistence of chronic disease, polypharmacy, and impaired organ functions makes geriatric population particularly susceptible to DDIs.49”
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The drug development landscape for combination therapy is becoming increasingly crowded with both symptomatic and disease-modifying applications.
“Thus, drug development landscape for combination therapy is becoming increasingly crowded with both symptomatic and disease-modifying applications.51”
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- Premisecitation
Mefloquine has demonstrated AChE and butyrylcholinesterase (BChE) inhibitory activities attributable to its quinoline ring.
“To note, other studies about mefloquine potential in AD, have demonstrated its AChE and butyrylcholinesterase (BChE) inhibitory activities, attributable to its quinoline ring, a well-known ChE pharmacophoric function.72”
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- Premisecitation
The idea of combining prolonged-release melatonin with AChEIs came from the observed relation between circadian rhythm dysfunction and neurocognitive disorders, a phenomenon observed as a consequence of decreased circulating melatonin level.
“The idea of the drug combination came from the observed relation between circadian rhythm dysfunction and neurocognitive disorders, a phenomenon that has been observed as consequence of the decreased circulating melatonin (11) level (Figure 6B).76,77”
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- Premisecitation
In the masitinib phase III clinical trial (NCT01872598), the drug combination reached the clinical phase without reported evidence of strong in vivo validation of synergistic or additive effects.
“Apparently, in this case, the drug combination reached the clinical phase without reported evidence of a strong in vivo validation of the synergic or additive effects involved.75”
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- Premisecitation
Melatonin in AD has been validated by in vivo and in vitro studies demonstrating a beneficial effect in reducing Aβ generation and deposition.
“Melatonin in AD has been validated by in vivo and in vitro studies demonstrating also a beneficial effect in reducing Aβ generation and deposition.79”
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- Premisecitation
The quercetin-dasatinib combination has been investigated for decreasing senescent cell burden in chronic illnesses such as diabetes, chronic kidney disease, and osteoarthritis.
“This combination has already been investigated for its effect on decreasing senescent cell burden in different chronic illnesses, such as diabetes, chronic kidney disease, and osteoarthritis.65”
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- Premisereasoning
As a result, the majority of papers on MTDLs only report in vitro activity data, sometimes with inadequate investigation of their multitarget mechanism of action.
“As a result, the majority of papers on MTDLs only report in vitro activity data, sometimes with inadequate investigation, of their multitarget mechanism of action.”
Quote in the paperSubstantial claim - Premisecitation
Codrugs can provide a high level of selectivity because the two molecules are rendered essentially inactive by covalent linking.
“This process can provide a high level of selectivity because the two molecules are rendered essentially inactive by the covalent linking.84”
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- Premisecitation
At low dose, mefloquine modulates the neuron-glia interface by inhibiting gap junction channels expressed in neurons and glial cells.
“Particularly, at low dose, mefloquine has been shown to modulate neuron-glia interface, by inhibiting the gap junction channels expressed in neurons and glial cells and providing cytoplasmic continuity and direct communication between neighboring cells.70”
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- Interpretationcitation
Combination therapies may prove increasingly successful in AD.
“These considerations, together with the increased recognition of complexity and the positive experience with other similarly complex diseases (cancer and human immunodeficiency virus-1), has led to believe that combination therapies may prove always more successful in AD.50”
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- Premisenone given
Melatonin combines chronobiotic and cytoprotective properties.
“Melatonin combines both chronobiotic and cytoprotective properties.”
Quote in the paperSubstantial claim - Premisenone given
Most trials for new polypharmacological approaches in AD are conducted in patients already receiving cholinesterase inhibitors, memantine, or both, and are thus add-on treatments.
“Most of the trials for new polypharmacological approaches in AD are conducted in patients already receiving cholinesterase inhibitors (ChEIs), memantine or both, and are thus new types of add-on treatments.”
Quote in the paperNot a substantial claim - Interpretationcitation
The polypharmacological effect produced by simultaneous delivery of the starting chemical entities in a codrug is unique and cannot be replicated by administering multiple drugs in combinations.
“Thus, the polypharmacological effect that can be produced by the simultaneous delivery of the starting chemical entities is unique and cannot be replicated by administering multiple drugs in combinations.84”
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- Premisecitation
Ibuprofen, as other NSAIDs, has demonstrated in in vivo studies the capability to delay the onset of AD.
“Ibuprofen (4), as other NSAIDs, has demonstrated in in vivo studies the capability to delay the onset of AD. 86”
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- Interpretationreasoning
The quercetin-dasatinib combination demonstrates reciprocal involvement of Src/Abl kinase and oxidative stress in the AD pathology network.
“This is a demonstration of the reciprocal involvement of Src/Abl kinase and oxidative stress in AD pathology network.”
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In codrugs, the two starting chemical entities are combined via a cleavable linker that, after enzymatic biotransformation, allows their release and individual biological effects against multiple pathways in the same target cells and at the same time.
“In fact, in codrugs the two starting chemical entities are combined via a cleavable linker, which, only after enzymatic biotransformation, allows their release and their individual biological effects against multiple pathways, in the same target cells and at the same time.84”
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- Premisecitation
Quercetin and dasatinib cotreatment is a senolytic drug combination repurposing currently in a phase I clinical trial (NCT04063124).
“Quercetin (5) and dasatinib (6) (Figure 5B) cotreatment is an example of a senolytic drug combination repurposing, currently in a phase I clinical trial (NCT04063124).61”
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As a chronobiotic, melatonin can modify phase and amplitude of the circadian sleep-wake rhythm.
“As a chronobiotic, melatonin can modify phase and amplitude of the circadian sleep-wake rhythm.”
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Peptide Aβ42 seems to promote mast cell degranulation and a consequent generalized inflammatory response.
“Peptide Aβ42 seems to promote mast cells degranulation and a consequent generalized inflammatory response.73”
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- Premisereasoning
Codrugs are the only feasible option when the two starting drugs do not share common functionalities and no structural amalgamation to provide a molecular chimera is possible.
“Of note, codrugs are the only feasible option when the two starting drugs do not share common functionalities and thus no structural amalgamation to provide a molecular chimera is possible.”
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The development of hybrids is not always preceded by a combination study of the parent single-target compounds.
“Apart from the previously reported examples, the development of hybrids is not always proceeded by the combination study of the parent single-target compounds.”
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Memantine (2) and galantamine (10) were able to reverse NMDA toxicity alone or in combination.
“This study showed how the two drugs were able to reverse NMDA toxicity alone or in combination.”
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- Premisecitation
The combination of memantine (2) and galantamine (10) resulted in a significant synergistic effect, even at subactive concentrations.
“In the latter case, they resulted in a significant synergistic effect, even at subactive concentrations.112”
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- Premisecitation
Co-administration of RS67333 (26) at 0.1 mg/kg and donepezil (1) at 0.3 mg/kg at subactive doses resulted in improved memory performances in mice.
“In this case, 26 (0.1 mg/kg) and 1 (0.3 mg/kg), when co-administrated at subactive doses, resulted in improved memory performances in mice.”
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NSAIDs might protect against AD by targeting underlying neuroinflammation.
“NSAIDs might protect against AD by targeting underlying neuroinflammation.95”
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- Premisecitation
ARN14140 (30) showed the best compromise between pharmacological and pharmacokinetic properties among the series.
“Among the series, shorter tethered ARN14140 (30) showed the best compromise between pharmacological and pharmacokinetic properties.”
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- Premisecitation
The ibuprofen-glutathione codrug (25, referred to as 15 in the text) has an improved effect compared with ibuprofen (4) and glutathione (23).
“In this way, the authors could successfully conclude that 15 has an improved effect compared with 4 and 23.97”
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- Interpretationcitation
Tacrine hemisuccinamide (22) has been proposed as the possible active principle in vivo.
“This has been proposed as the possible active principle in vivo.94”
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In behavioral tests of long-term spatial memory, animals treated with ibuprofen-glutathione codrug (25) performed better than those treated with ibuprofen (4) and glutathione (23) singularly.
“The data obtained by behavioral tests of long-term spatial memory demonstrated that animals treated with 25 performed better than those treated with 4 and 23 singularly.”
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- Premisecitation
Tacrine has been widely exploited as a starting fragment of hybrids able to combine AChE inhibition with other additional effects and reduced hepatotoxicity, thanks to its low molecular weight and high synthetic accessibility.
“In spite of that, thanks to its low-molecular weight and high synthetic accessibility, 16 has been widely exploited as a starting fragment of hybrids able to combine AChE inhibition with other additional effects and endowed with reduced hepatotoxicity.91”
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- Interpretationreasoning
Hybrids could be cost effective due to simpler pharmacodynamic and pharmacokinetic property evaluation, as the profile results from a single chemical entity rather than from a combination of two drugs.
“In the same way as codrugs, hybrids could be cost effective due to simpler pharmacodynamic and pharmacokinetic property evaluation, as the profile results from a single chemical entity, rather than from a combination of two drugs.”
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Aβ protein was less expressed in the cerebral cortex of mice treated with 25 than in mice treated with 4.
“Moreover, histochemical studies revealed that Aβ protein was less expressed in cerebral cortex of mice treated with 25 than in mice treated with 4.”
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- Premisecitation
Administration of contilisant (36) at 1 mg/kg restores cognitive deficit in LPS-treated mice.
“In vivo efficacy studies showed that administration of 36 at 1 mg/kg is able to restore the cognitive deficit in lipopolysaccharide (LPS)-treated mice.120”
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- Premisecitation
The single-molecule pharmacokinetic profile of hybrids may allow avoidance of drug-drug interactions (DDI), which occur more frequently in AD patients due to coexistence of chronic disease, therapies, and impaired organ functions.
“Furthermore, the single-molecule pharmacokinetic profile of hybrids, from administration to secretion, may allow to avoid DDI, that occur more frequently in AD patients, because of the coexistence of chronic disease, therapies, and impaired organ functions.49”
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- Premisecitation
Hybrids 50, 51 and 52, which have multitarget profiles, were investigated in clinical trials.
“Examples of hybrids with multitarget profiles investigated in clinical trials A) 50; B) 51; C) 52”
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Selected hybrid 49 possesses the highest affinity on 5-HT6R.
“In addition, selected hybrid 49 also possessed the highest affinity on 5-HT 6 R.”
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Compound 39, unlike nifedipine (38), does not show a significant vasorelaxant effect in vivo.
“In addition, contrary to 38, 39 did not show in vivo a significant vasorelaxant effect.125”
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- Premisecitation
The tacrine-cannabinoid hybrids show higher inhibition of ChE compared with tacrine (16) in vitro.
“Overall, in vitro assays showed higher inhibition of ChE by the hybrids compared with 16.”
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- Premisenone given
The combination of masitinib and acetylcholinesterase inhibitors was investigated in a Phase III clinical trial.
“B) Pase III clinical trial: combination of masitinib and AChE inhibitors;”
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All tested tacrine-cannabinoid hybrids reduce Aβ aggregation, unlike tacrine (16).
“Different from 16, all the tested hybrids showed effect in reducing Aβ aggregation.”
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- Premisecitation
Higher concentrations of biometals in Aβ plaque deposits in AD patients' brains support the role of metal dyshomeostasis in AD pathogenesis.
“In AD patients' brains, higher concentrations of biometals in Aβ plaque deposits support the role of metal dyshomeostasis in AD pathogenesis.126”
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- Premisecitation
Compound 47 confirms its procognitive potential in a scopolamine-induced cognitive deficit rat model.
“By using scopolamine-induced cognitive deficit rat model, 47 confirmed its procognitive potential.138”
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Compound 39 restores cognitive impairment induced by LPS in vivo.
“From in vivo results, 39 was identified as a promising lead molecule thanks to its ability to restore cognitive impairment induced by LPS.”
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- Premisecitation
Indole-based melatonin-N-benzylamine hybrids promote the development of neural stem cells into neuronal phenotypes.
“Interestingly, among those small molecules, indole-based melatonin-N-benzylamine hybrids, have been proven to effectively promote the development of neural stem cells into neuronal phenotypes.128”
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- Premisenone given
The combination of mefloquine and donepezil was investigated in a Phase I clinical trial.
“A) Phase I clinical trial: combination of mefloquine and donepezil ;”
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In a phase III clinical trial in China (NCT03715114), the treatment produced a statistically significant improvement in cognitive function in mild-to-moderate Alzheimer's disease patients, evident as early as week 4 and at each subsequent follow-up assessment visit.
“phase III clinical trial in China (NCT03715114) showing a statistically significant improved cognitive function in mild-to-moderate AD patients, as early as week 4 and further each follow-up assessment visit.150”
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- Premisecitation
The tested tacrine-cannabinoid hybrids have significantly higher in vivo efficacy at 0.1 mg/kg than the parent molecules tacrine (16) and the hCB2R agonist (43).
“Eventually, in vivo efficacy of the tested hybrids resulted significantly higher (0.1 mg/kg), than for the parent molecules 16 and 43.”
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Currently ongoing clinical trials are often based on drugs with multitarget profiles or drug combinations.
“This trend is mirrored in the currently ongoing clinical trials, often based on drugs with multitarget profiles or drug combinations.17”
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The developed tacrine-cannabinoid hybrids show no hepatotoxicity effect at 3 mg/kg dose.
“Keeping in mind the hepatotoxicity of tacrine, it is extremely relevant that the developed hybrids showed no hepatotoxicity effect at 3 mg/kg dose.134”
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In patients with moderate AD, combination therapy of donepezil (1) and 5-HT6R antagonist idalopirdine shows superior effect over donepezil monotherapy.
“Recent clinical trials in patients with moderate AD, have shown a superior effect of the combination therapy of donepezil (1) and 5-HT 6 R antagonist idalopirdine over monotherapy with donepezil.139”
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The tacrine-cannabinoid hybrids display an immunomodulatory effect similar to the parent hCB2R agonist (43), despite lower hCB2R affinity.
“Conversely, despite the significantly lower hCB2R affinity compared with 43, the hybrids displayed an immunomodulatory effect similar to the parent molecule (43).”
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- Premisecitation
GV-971 (52) has preclinical evidence of a multitarget mechanism of action, acting on neuroinflammation, Aβ plaques, neurofibrillary tangles, mitochondrial function, and cholinergic disruption.
“The same authors have also shown preclinical evidence of a multitarget mechanism of action for 52, which should not only act by reversal of neuroinflammation, but also on Aβ plaques, neurofibrillary tangles, mitochondrial function, and cholinergic disruption.149”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [149] source
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- May combine two claims. 55
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 12
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FindingcitationPhase I clinical trial confirmed the safety of the cromolyn-ibuprofen combination and positive pharmacokinetic studies in healthy elderly volunteers, allowing rapid transition to phase III.
“Indeed, phase I clinical trial has confirmed the safety of the drug combination and positive pharmacokinetic studies in healthy elderly volunteers, which has allowed rapid transition to phase III.60”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [60] source
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Findingown dataThe extension of THN201's pharmacological profile is reflected in higher mnemonic fluidity during cognitive tests and greater power in the electroencephalography gamma band related to cognitive activity.
“This extension is consistently reflected in a higher mnemonic fluidity observed during cognitive tests and a greater power in the electroencephalography gamma band related to cognitive activity.”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationIn a double transgenic APP/PS1 mouse model with severe amyloid pathology, the memantine-melatonin combination restored episodic memory and efficiently reduced Aβ aggregates and biomarkers of neuroinflammation compared with memantine or melatonin alone.
“The results showed restoration of the episodic memory and an efficient reduction of Aβ aggregates and biomarkers of neuroinflammation, when compared with memantine or melatonin alone.80”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [80]
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FindingcitationThe cromolyn-ibuprofen study showed promotion of Aβ42 uptake in microglia by cromolyn and its superior activity, in combination with ibuprofen, in reducing Aβ level via induction of a neuroprotective microglia activation state favoring Aβ phagocytosis.
“The study showed the promotion of Aβ42 uptake in microglia by 3 and its superior activity, in combination with 4, in reducing Aβ level thanks to the induction of a neuroprotective microglia activation state favoring Aβ phagocytosis.”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationIn APP/PS1 mutant transgenic mouse models, the quercetin-dasatinib combination acts by selective removal of senescent cells from the Aβ plaque environment, leading to reduced proinflammatory cytokine secretion and decreased Aβ concentration, with overall amelioration of cognitive disturbances.
“Successful repurposing in AD is supported by in vivo studies in amyloid precursor protein (APP)/PS1 mutant transgenic mouse models.The combination seems to act by the selective removal of senescent cells from the Aβ plaque environment, leading to a reduction of proinflammatory cytokine secretion and a decrease of Aβ concentration, with an overall amelioration of cognitive disturbances.66”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [66] source
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Findingown dataCodrug 20 is less potent as AChEI and BChE inhibitor than tacrine, but it showed no neurotoxic effects on hippocampal cell line and displayed neuroprotective effects against glutamate-induced oxidative stress, not observed with the drug combination.
“It was observed that 20 is less potent as AChEI and BChE inhibitor than 16, but it showed no neurotoxic effects on hippocampal cell line, while displaying neuroprotective effects against glutamate-induced oxidative stress, not observed with the drug combination.”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationBoth coadministration of tacrine and silybin B and codrug 20 showed in vivo a hepatoprotective effect and an improvement of cognitive impairment.
“Importantly, both 16 and 17 coadministration and 20, showed in vivo a hepatoprotective effect and an improvement of the cognitive impairment.93”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [93]
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Findingown dataIn vitro stability studies showed that all ibuprofen-lipoic acid codrugs (13-15) had more rapid hydrolysis in brain tissue than in plasma, but codrug 13 had good stability in both conditions.
“The results highlighted that even if all the codrugs showed a more rapid hydrolysis in brain tissue than in plasma, 13 has a good stability in both conditions.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEvaluation of 22 in a hematopoietic stem cells-based assay confirmed the in vivo low toxicity and suggested a crucial role of the hemisuccinamide linker, being nontoxic and probably critical in conferring hepatoprotective properties.
“In particular, an evaluation of 22 in hematopoietic stem cells-based assay, not only confirmed the in vivo low toxicity, but also suggested a crucial role of the hemisuccinamide linker, being nontoxic and probably critical in conferring hepatoprotective properties.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Interpretationnone givenA target pair is validated for polypharmacology when consistent and reliable in vitro and in vivo models show additive or synergistic effects from concomitant modulation.
“In a polypharmacology context, we should consider validated those target pairs which, when investigated in consistent and reliable in vitro and in vivo models, demonstrate additive or synergistic effects resulting from a concomitant modulation.”
Quote in the paperSubstantial claim- Rests on an assumption: Additive or synergistic effects observed in in vitro and in vivo models for a target pair predict clinical efficacy in AD.
May combine two claims.
PremisecitationIn a multifactorial pathologic condition, inhibition of one pathway is normally compensated by higher activation of other pathways, which may lead to a resistance phenotype and higher dose usage, increasing the risk of side effects from off-target modulation.
“In a multifactorial pathologic condition, the inhibition of one pathway is normally compensated by higher activation of other pathways.This may lead to a resistance phenotype and result in a higher dose usage, which, in turn, may increase the risk of side effects, as a consequence of off-target modulation.7”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] source
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PremisereasoningThe available therapeutic arsenal for AD is not effective, treating just symptoms and not stopping disease progression.
“Despite the advancements toward pathological mechanism elucidation, the available therapeutic arsenal is not effective, treating just symptoms and not stopping disease progression.”
Quote in the paperSubstantial claimMay combine two claims.
Premisenone givenThe available drugs for AD are single-target small molecules that act by inhibiting acetylcholinesterase (AChE) or blocking the N-methyl-D-aspartate receptor (NMDAR).
“Notwithstanding the clear multifactorial nature of AD, the available drugs are single-target small molecules that act by inhibiting acetylcholinesterase (AChE) or blocking the N-methyl-D-aspartate receptor (NMDAR).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningMTDLs and fixed-dose combinations do not permit dose regimen adjustment but account for a simplified therapeutic regimen.
“This not the case for both MTDLs and fixed-dose combinations, which, in turn, account for a simplified therapeutic regimen.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAs a cytoprotective molecule, melatonin reverses inflammatory damage, scavenges free radicals, and facilitates the immune response.
“As a cytoprotective molecule, melatonin reverses inflammatory damage, scavenges free radicals, and facilitates the immune response.78”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [78] source
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PremisecitationIbuprofen prevents COX-mediated prostaglandin E2 responses in synapses, reduces microglia overactivation and Aβ deposition, and restores Aβ phagocytosis by microglia.
“On the other side, 4, a nonsteroidal anti-inflammatory drug (NSAID) and a cyclooxygenase (COX) inhibitor, prevents COX-mediated prostaglandin E2 responses in synapses, reduces microglia overactivation and Aβ deposition, restoring Aβ phagocytosis is by microglia.57,58”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [57]
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- cites [58]
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PremisecitationDonepezil is an AChEI currently used as first-line treatment for AD.
“1 is an AChEI currently used as the first-line treatment for AD.68”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [68]
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PremisecitationMasitinib is an oral and selective inhibitor of Fyn, a tyrosine kinase involved in the survival, migration, and activity of mast cells.
“Masitinib (8) (Figure 6B) is an oral and selective inhibitor of Fyn, a tyrosine kinase involved in the survival, migration, and activity of mast cells.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationCrucial factors in the efficiency of NSAIDs as neuroprotective drugs are their high percentage of binding to plasma proteins, low distribution volume, and blood-brain barrier penetration.
“In particular, crucial factors in the efficiency of NSAIDs as neuroprotective drugs are their high percentage of binding to the plasma proteins and low distribution volume, as well as blood-brain barrier (BBB) penetration.87”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [87]
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PremisecitationNeuroinflammation is one of the major AD pathological processes and a drug discovery research priority.
“Neuroinflammation is one of the major AD pathological processes and a drug discovery research priority.52”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52]
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PremisecitationCromolyn had shown effects on neuroinflammation by stabilizing mast cell membranes and inhibiting microglia activation, and on Aβ levels by directly interacting with Aβ oligomers.
“Both drugs had been already investigated separately in vivo for their potential to combat neuroinflammation in AD: 3 had shown effects on neuroinflammation by stabilizing mast cell membranes and inhibiting microglia activation, 55 and on Aβ levels by directly interacting with Aβ oligomers.56”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [55]
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- cites [56]
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PremisecitationQuercetin is a potent natural antioxidant used as a dietary supplement for metabolic and inflammatory disorders, as well as AD.
“On the other side, 5 is a potent natural antioxidant used as a dietary supplement for metabolic and inflammatory disorders, as well as AD.64”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [64]
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PremisereasoningHybrids exert a dual effect acting simultaneously on two biological targets as a single chemical entity because they do not undergo enzymatic cleavage.
“As hybrids do not undergo enzymatic cleavage, they exert a dual effect acting simultaneously on two biological targets as a single chemical entity.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Premisenone givenSo far, the development of MTDLs for AD has been mostly pursued in academia, where in vivo efficacy studies may often be cost-prohibitive and limited by ethical constraints.
“So far, the development of MTDLs for AD has been mostly pursued in academia, where in vivo efficacy studies may often be cost-prohibitive and limited by ethical constraints.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenNowadays, there are no examples of ongoing clinical trials involving codrugs for AD, but some promising in vivo results suggest that AD drug development might evolve in this direction.
“Nowadays, there are no examples of ongoing clinical trials involving codrugs for AD, but some promising in vivo results suggest that AD drug development might evolve in this direction.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningThe outcomes of drug combinations in preclinical or clinical studies provide strong validation of target networking and might be a source of inspiration for MTDLs de novo design.
“The outcomes of drug combinations in preclinical or clinical studies, besides providing a strong validation of target networking, might be a source of inspiration for MTDLs de novo design.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationDasatinib is a thiazole-based Src/Abl kinase inhibitor approved by the FDA for myelogenous leukemia.
“6 is a thiazole-based Src/Abl kinase inhibitor approved by the FDA for myelogenous leukemia.63”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [63]
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Premisenone givenFyn is upregulated in AD, and Fyn kinase inhibition by masitinib can modulate pathological pathways such as tau phosphorylation and neurofibrillary tangles formation.
“Additionally, Fyn is upregulated in AD, and Fyn kinase inhibition by 8 can modulate different pathological pathways, such as tau phosphorylation and neurofibrillary tangles formation.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMefloquine is registered for malaria chemoprophylaxis, and its neurological side effects have suggested repurposing for CNS diseases.
“Mefloquine is a drug registered for malaria chemoprophylaxis, but its neurological side effects have suggested its repurposing for CNS diseases.69”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [69]
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PremisecitationIncreased cytosolic calcium level is involved in AD pathogenesis by facilitating Aβ formation and activating the apoptotic cascade through mitochondria.
“Indeed, increased cytosolic calcium level is involved in the pathogenesis of AD, by facilitating Aβ formation and activating the apoptotic cascade through the mitochondria. 124”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [124] source
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Premisecitation5-HT4 receptor agonists promote the nonamyloidogenic cleavage of APP and favor the production of the neurotrophic protein sAPPα.
“Furthermore, 5-HT 4 receptor (5-HT 4 R) agonists are able to promote the nonamyloidogenic cleavage of the APP and to favor the production of the neurotrophic protein sAPPα.106”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [106] source
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PremisecitationDonecopride (27) displays nanomolar dual-binding site AChE inhibitory effects and partial 5-HT4R agonist activity.
“Successfully, 27 displayed nanomolar dual-binding site AChE inhibitory effects and partial 5-HT 4 R agonist activity.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [109]
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- cites [110]
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PremisecitationHDACs are epigenetic modulators that deacetylate lysine residues in histone and nonhistone substrates; their inhibition is of interest for neurodegenerative disorders, as HDAC2 reduces transcription of CREB-regulated genes involved in learning and memory, and HDAC6 targets α-tubulin facilitating amelioration of tau pathogenesis.
“HDACs are epigenetic modulators that deacetylate lysine residues in histone and nonhistone substrates and their inhibition has attracted much interest for the treatment of neurodegenerative disorders, as several isoforms seem to be implicated in AD memory-related dysfunction: HDAC2 is a nuclear isoform that reduce transcription of CREB-regulated genes involved in learning and memory, HDAC6 targets”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [118] source
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Premisenone given(R)-α-lipoic acid is a dithiol that binds lysine residues of mitochondrial α-keto acid dehydrogenase complex and can easily cross the BBB and accumulate in all neuronal cell types.
“12 is a dithiol that binds lysine residues of mitochondrial α-keto acid dehydrogenase complex.It can easily cross the BBB and accumulate in all neuronal cell types.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenThe active form of lipoic acid is its reduced form, dihydrolipoic acid, which is produced in mitochondria.
“Anyway, the active form of lipoic acid is its reduced form, the dihydrolipoic acid, which is produced in mitochondria.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSilybin B is one of the main components of Carduus marianus extract, proposed as an anti-inflammatory and anticancer agent, and is considered an interesting scaffold for AD drug discovery due to its neuroprotective effects.
“17 is one of the main components of the Carduus marianus extract (Figure 9), proposed as an anti-inflammatory and anticancer agent.It is considered an especially interesting scaffold for AD drug discovery, thanks to its neuroprotective effects.92”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [92]
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PremisecitationMemagal (29) and some related hybrids are nanomolar inhibitors of AChE and display micromolar affinities for NMDAR.
“Memagal (29), with a six-carbon linker, and some of the reported hybrids were nanomolar inhibitors of AChE and displayed micromolar affinities for NMDAR.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [113]
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PremisecitationMolecular weight is a physicochemical parameter fundamental for CNS penetration and for the overall profile of drugs against neurodegenerative diseases.
“Clearly, molecular weight is a physicochemical parameter fundamental for CNS penetration and for the overall profile of drugs against neurodegenerative diseases.103,104”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [103]
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- cites [104] source
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PremisecitationInhibition of PDE5 increases cyclic guanosine monophosphate level, which is decreased in AD patients, by activating CREB and favoring the inactive form of GSK3β, thus decreasing phosphorylated tau levels.
“Inhibition of PDE5 increases cyclic guanosine monophosphate level, significantly decreased in AD patients by direct and/or indirect activation of cAMP-response element binding protein (CREB) and by favoring the inactive form of glycogen synthase kinase 3 (GSK3β), thus decreasing the levels of phosphorylated tau.117”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [117]
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PremisecitationARN14140 (30) prevented cognitive impairment and showed neuroprotective potential in mice treated with the amyloidogenic fragment 25-35 of the Aβ peptide.
“30 was then selected for in vivo studies in mice treated with the amyloidogenic fragment 25 to 35 of the Aβ peptide, in which it demonstrated its role in preventing the cognitive impairment and its neuroprotective potential (Figure 12A).114”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [114]
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PremisecitationIbuprofen-glutathione codrug (25) has good stability in human plasma and free radical-scavenging activity similar to glutathione (23), in a time- and concentration-dependent way.
“In vitro evaluation of 25 highlighted a good stability in human plasma and showed a free radical-scavenging activity similar to 23, in a timeand concentration-dependent way.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [97]
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Premisecitation(R)-α-lipoic acid has been proposed as a lead structure for AD drug discovery and studied in several clinical trials.
“In contrast, (R)-α-lipoic acid (12) (Figure 8), already in the market as dietary supplement, has been proposed as a lead structure for AD drug discovery 88 and studied in several clinical trials (NCT01058941, NCT00090402, NCT00117403).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [88]
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHybrids can be obtained by linking, fusing, or merging strategies.
“As first enunciated by Morphy and Rankovic 19 in 2005, hybrids can be obtained by linking, fusing, or merging strategies (Figure 7).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19]
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PremisecitationCompound 28 has increased inhibition of Aβ aggregation, potent nanomolar inhibition of AChE, affinity for the σ1 receptor, and lower affinity for the 5-HT4R.
“The selected compound 28 eventually resulted in an increased inhibition of Aβ aggregation in addition to a potent nanomolar inhibition of AChE and affinity for the σ1 receptor, associated with a lower affinity for the 5-HT 4 R.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [111]
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PremisereasoningIn the tacrine-silybin codrug 20, the AChE-inhibiting fragment can be released by exploiting different bond stability, penetrating the BBB and acting at the brain level.
“By exploiting the different bond stability, the AChE-inhibiting fragment (19) can be released, penetrating the BBB, and acting at the brain level.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationGlutathione is one of the most prevalent antioxidants in the brain and protects against ROS, redox metal ions, reactive lipid peroxidation products, and other electrophiles that could be dangerous for cell viability.
“Glutathione (23) is one of the most prevalent antioxidants in the brain and is able to protect against reactive oxygen species (ROS), redox metal ions, reactive lipid peroxidation products, and other electrophiles that could be dangerous for cell viability.96”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [96]
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PremisecitationCM-414 (33) is a first-in-class dual inhibitor of PDE5 and HDAC, proposed as a potential therapeutic tool for AD.
“33 is a first-in-class dual inhibitor of phosphodiesterase-5 (PDE5) and histone deacetylases (HDAC), recently proposed as a potential therapeutic tool for AD.115,116”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [115]
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- cites [116]
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PremisecitationDihydrolipoic acid activates choline acetyltransferase, chelates redox-active transition metals, increases the amount of reduced glutathione, and downregulates redox-sensitive inflammatory processes.
“Dihydrolipoic acid activates choline acetyltransferase, chelates redox-active transition metals, increases the amount of the reduced form of glutathione, and downregulates the redox-sensitive inflammatory processes.89”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [89] source
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PremisecitationBlocking of central H3R induces the release of procognitive neurotransmitters, including ACh, which is the basis for H3R involvement in cognitive processes.
“Involvement of H 3 R in the cognitive process is based on the fact that blocking of central H 3 R induces the release of procognitive neurotransmitters, including ACh. 121”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [121]
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone givenTacrine was the first AChEI registered for AD but was withdrawn from the market due to hepatotoxic side effects.
“Tacrine (16) was the first AChEI registered for AD, but was withdrawn from the market due to its hepatotoxic side effects.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationGV-971 (52), sodium oligomannate, suppresses gut dysbiosis and associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation, and reverses cognition impairment.
“52, sodium oligomannate derived from marine algae, has been shown to suppress gut dysbiosis and the associated phenylalanine/isoleucine accumulation, to harness neuroinflammation and reverse cognition impairment.148”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [148] source
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Premisenone givenThe combination of melatonin, memantine and acetylcholinesterase inhibitors was investigated in a concluded clinical trial.
“concluded clinical trial: combination of melatonin, memantine and AChE inhibitors”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationLadostigil (50) is a low-molecular-weight hybrid resulting from merging rasagiline and rivastigmine structures, combining MAO inhibition and AChEI activity, intended for AD comorbidity with extrapyramidal disorders and depression.
“The structure of 50 results from the rational merging of a large portion of the structures of the MAO B inhibitor rasagiline and the AChEI rivastigmine (9), thereby leading to a low-molecular-weight hybrid compound 50, which combines the neuroprotective effects of MAO inhibition and AChEI activity in a single molecule, and is intended for the treatment of AD comorbidity with extrapyramidal”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [141]
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PremisecitationThe use of metal-chelating agents to inhibit the production or accumulation of Aβ plaques has been proposed.
“Therefore, the use of appropriate metal-chelating agents to inhibit the production or accumulation of Aβ plaques has been proposed.126”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [126]
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Premisecitation8-Hydroxyquinoline (40) is a key scaffold due to its moderate chelating properties and capability to extract metals from Aβ aggregates.
“Among those, 8-hydroxyquinoline (40) represents a key scaffold, thanks to its moderate chelating properties and suitable capability to extract metals from Aβ aggregates.127”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [127]
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PremisecitationLadostigil (50) was safe and well-tolerated but did not delay the progression of dementia in a phase II clinical trial in patients with mild cognitive impairment.
“It was safe and well-tolerated, but, unfortunately, it did not delay the progression of dementia.142”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [142] source
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PremisecitationAnavex 2-73 (51) may target protein misfolding by modulating GSK3β, inhibit oxidative stress and mitochondrial dysfunction, and reduce inflammation and cellular stress.
“In addition, it has been demonstrated that 51 may also target protein misfolding by modulating GSK3β, inhibit oxidative stress and mitochondrial dysfunction, and reduce inflammation and cellular stress.136”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [136]
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Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenTarget validation is a step that crucially determines the final outcome of MTDD.
“As discussed, target validation is a step that crucially determines the final outcome.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationAnavex 2-73 (51) is safe and well-tolerated in a phase II clinical study, with significant association between dosage and cognitive and functional improvements.
“Compound 51 has proven to be safe and well-tolerated throughout a phase II clinical study, which showed significant association between the dosage of 51 and cognitive and functional improvements.145”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [145]
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PremisecitationThe combination of pharmacophores tacrine (16) and 5-HT6R antagonist 48 preserves high affinity for selected biological targets and improves activity against AChE compared with tacrine (16).
“It is worth to note that the unique combination of pharmacophores 16 and 48, not only preserved their high affinity for the selected biological targets, but also improved the activity against AChE compared with 16.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [140] source
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Additive or synergistic effects observed in in vitro and in vivo models for a target pair predict clinical efficacy in AD.
“In a polypharmacology context, we should consider validated those target pairs which, when investigated in consistent and reliable in vitro and in vivo models, demonstrate additive or synergistic effects resulting from a concomitant modulation.”
The paper relies on this without support.
Supplementation of physiological antioxidants and free radical scavengers can be another therapeutic strategy in AD.
“Furthermore, supplementation of physiological antioxidants and free radical scavengers can be another therapeutic strategy in AD.”
The paper relies on this without support.
Activation of serotonin 5-HT4 receptor and blockage of 5-HT6 receptor enhance ACh release, suggesting that modulation of the serotoninergic system could restore the cholinergic neurotransmission deficit observed in AD.
“Activation of serotonin 5-HT 4 receptor (5-HT 4 R) and blockage of 5-HT 6 receptor (5-HT 6 R) have been reported to enhance ACh release, suggesting that modulation of serotoninergic system could efficiently restore the cholinergic neurotransmission deficit observed in AD.”
The paper relies on this without support.
Combination of sildenafil (31) and vorinostat (32) shows significant synergy in inducing histone acetylation, confirmed by in vivo models.
“Combination of sildenafil (31), a PDE5 inhibitor, and of vorinostat (32), a pan-HDAC inhibitor (Figure 12B), showed, in fact, significant synergy in inducing histone acetylation, which was also confirmed by in vivo models.”
The paper relies on this without support.
Chronic treatment of Tg2576 mice with CM-414 (33) diminished brain Aβ and tau levels, increased the inactive form of GSK3β, and reversed cognitive deficits.
“Chronic treatment of Tg2576 mice with 33 diminished brain Aβ and tau levels, increased the inactive form of GSK3β, and reversed the cognitive deficits.”
The paper relies on this without support.
The quinoline-indole hybrids have antioxidant effects, biometal chelation activity, Aβ aggregation modulation, neurotrophic, and neuroprotective properties in vitro.
“In vitro evaluation revealed that all the hybrids had antioxidant effects, biometal chelation activity, Aβ aggregation modulation, neurotrophic, and neuroprotective properties.”
The paper relies on this without support.
In vivo assays demonstrated hippocampal cell proliferation in living adult mice after administration of the quinoline-indole hybrids.
“Furthermore, in vivo assays demonstrated hippocampal cell proliferation in living adult mice, after compound administration.”
The paper relies on this without support.
Chronic oral administration of compound 42 substantially ameliorated cognitive and spatial memory deficits in APP/PS1 AD mice and noticeably reduced overall cerebral Aβ deposits.
“Pharmacodynamics studies revealed that chronic oral administration of 42 substantially ameliorated the cognitive and spatial memory deficits in APP/PS1 AD mice and noticeably reduced overall cerebral Aβ deposits.”
The paper relies on this without support.
In AD patients, L-tryptophan intake is inversely correlated with learning impairment and Aβ accumulation.
“Studies on patients with AD have shown an inverse correlation between L-tryptophan (L-Trp, 46) intake and learning impairment and Aβ accumulation (Figure 15A).”
The paper relies on this without support.
Most tacrine-tryptophan hybrids exhibit moderate inhibitory activity against neuronal nitric oxide synthase and good ability to inhibit Aβ42 self- and AChE-induced aggregation.
“Most of the hybrids exhibited moderate inhibitory activity against neuronal nitric oxide synthase and good ability to inhibit Aβ42 self-and AChE-induced aggregation.”
The paper relies on this without support.
Tacrine-tryptophan hybrids show excellent balanced ChE inhibition, with potentially greater clinical efficacy and fewer side effects compared with previously reported derivatives.
“In comparison with the previously reported derivatives, the tacrinetryptophan hybrids showed excellent balanced ChE inhibition, with potentially greater clinical efficacy and fewer side effects.”
The paper relies on this without support.
Anavex 2-73 (51) binds muscarinic and σ1 receptors with affinities in the low micromolar range.
“Anavex 2-73 (51) (Figure 16B) is a small molecule, which is able to bind muscarinic and σ1 receptors with affinities in the low micromolar range.”
The paper relies on this without support.
Anavex 2-73 (51) reverses scopolamine-induced long- and short-term memory deficits in in vivo studies.
“In in vivo studies, 51 has been shown effective in reversing scopolamine-induced long-and short-term memory deficits.”
The paper relies on this without support.
A mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression has been provided.
“Although the mechanism of action of GV-971 remains unclear, a mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression has been provided.”
The paper relies on this without support.
In AD mouse models, alteration of gut microbiota composition leads to peripheral accumulation of phenylalanine and isoleucine, stimulating differentiation and proliferation of pro-inflammatory Th1 cells.
“In AD mouse models, alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T-helper 1 cells (Th1).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The development of multi-target ligands, compounds capable of interacting with more than one relevant target in the pathogenesis of Alzheimer's disease, is gaining growing relevance.
“the development of multi-target ligands (MTDLs), or compounds capable of interacting with more than one relevant target in the pathogenesis of the disease, is gaining growing relevance [57].”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [57]
Multi-target ligand molecules designed to preserve interaction with specific binding sites potentially act on several fronts, allowing a more effective slowdown of the neurodegenerative process.
“These molecules, designed to preserve their interaction with specific binding sites, potentially act on several fronts, allowing a more effective slowdown of the neurodegenerative process [57].”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [57]
One of the most followed multi-target ligand design strategies consists in combining different pharmacophores provided by specific biological activities, linked together by suitable linkers or directly fused/merged, into a single molecule.
“One of the most followed MTDL design strategies consists in combining different pharmacophores provided by specific biological activities, linked together by suitable linkers or directly fused/merged, into a single molecule.”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [57]
Alzheimer's disease and other neurodegenerative diseases are based on a few etiological events intertwined with each other; therefore, a more holistic approach could contribute to development of more resolutive therapies.
“these kinds of pathologies are based on a few etiological events intertwined with each other; therefore, a more holistic approach could contribute to the development of more resolutive therapies.”
From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [57]
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Ibuprofen-glutathione codrug is identified as both 15 and 25
MinorThe paper identifies the ibuprofen-glutathione codrug as compound 25, but the conclusion of the same discussion calls it compound 15. Compound 15 is identified elsewhere as an ibuprofen-lipoic acid codrug.
“In this way, the authors could successfully conclude that 15 has an improved effect compared with 4 and 23.97”
“Pinnen et al 97 designed and synthesized an ibuprofen-glutathione codrug (25) by linking a prodrug form of 23, that is, glutathione dimethyl ester (24) and ibuprofen (4) (Figure 10).”
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THE ANTICHOLINESTERASE ACTIVITY OF MEFLOQUINE
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- Medicine NLo.https://www.ncbi.nlm.nih.gov/mesh/?term=polypharmacology
- Decker M, 2017, Design of Hybrid Molecules for Drug Development
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Inflammatory Processes in Alzheimer’s Disease—Pathomechanism, Diagnosis and Treatment: A Review
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“This is why the term Multi-Target Directed Ligand (MTDL) was coined [374,375].”
BackgroundMolecular hybridization: a powerful tool for multitarget drug discovery
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Self-citationChalcone and its analogs: Therapeutic and diagnostic applications in Alzheimer’s disease
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Quinones as Neuroprotective Agents
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“, cancer (Wermuth, 2004), Alzheimer’s disease (Wang et al., 2017b; Albertini et al., 2021), and infectious diseases (Morphy et al.”
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“In this context, treatment strategies for this disease have been proposed to shift from single to multiple targets, and a vast array of new therapeutic approaches for AD is under investigation [9, 10].”
BackgroundAI-Driven Polypharmacology in Small-Molecule Drug Discovery
Abdelsayed, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26146996 · Cited by 49 · see citing works
“…therapies have largely failed in AD, prompting a shift toward multi-target strategies such as combination therapies and multi-target-directed ligands (MTDLs), which integrate activities like cholinesterase inhibition and antioxidant or anti-amyloid effects within one molecule [2,15–17].”
Unveiling the Multitarget Anti-Alzheimer Drug Discovery Landscape: A Bibliometric Analysis
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“In this light, Bolognesi and coworkers have proposed the following flowchart to validate a given target combination for a de novo multitarget approach: (i) identification of selective and nearly equipotent reference compounds for each selected target; (ii) demonstration of lack of cytotoxicity of the combination of re…”
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Polypharmacological Approaches for CNS Diseases: Focus on Endocannabinoid Degradation Inhibition
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“The pharmaceutical agents can be combinations of multiple drugs binding to different targets, an approach called drug combinations, or single drugs binding to multiple targets, defined as multitarget ligands [5].”
BackgroundNeurodegenerative disorders—Searching for targets and new ways of diseases treatment
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“Albertini et al.(10) attract the attention of the readers to polypharmacological approaches in the development of drugs for complex neurodegenerative disorders such as Alzheimer's disease.”
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“In order to complement the traditional possibility to conceive MTDL by linking [22], fusing or merging structure, we have recently prepared pleiotropic prodrug [31].”
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“Therefore, the construction of multifunctional disease-modifying agents that can act simultaneously on several targets thought to be involved in the pathogenesis of the disease is a current trend in the design of new effective treatments of these pathologies [6,7].”
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Phytomedicine for neurodegenerative diseases: The road ahead
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BackgroundGauging the role and impact of drug interactions and repurposing in neurodegenerative disorders
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“However, most of these single target-based drugs could be able to provide symptomatic relief (Albertini et al., 2021; Pravin & Jozwiak, 2022) and miserably failed in halting the progression of AD.”
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“) [40]. σ 1R appears to be a promising target for AD treatment due to its implication in the pathogenesis of the disease and some ligands of these receptors are currently in Such indole Pharmaceutics 2023 , 15 , 2382 9 of 13 clinical trials (vide infra), alone or in combination with drugs targeting other targets.”
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“[324] One of the most popular MTDL design methodologies is integrating many pharmacophores offered by certain biological activities into a single molecule, either directly or by means of suitable linkers.”
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“Polypharmacology that uses a single chemical to selectively bind to multiple drug targets has emerged as a new paradigm in drug discovery 5–10 .”
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- Authors
- Albertini, C., Salerno, A., de Sena Murteira Pinheiro, P., & Bolognesi, M. L.
- Affiliations
- University of Bologna (IT)
- Department of Pharmacy and Biotechnology Alma Mater Studiorum–University of Bologna Bologna Italy
- Venue
- Medicinal Research Reviews
- Publisher
- Wiley
- Published
- 2020-06-19
- Volume
- 41
- Issue
- 5
- Pages
- 2606-2633
- ISSN
- 0198-6325 (ISSN-L)
- 1098-1128
- OpenAlex
- W3035889410
- Cited by
- 179
- References
- 157
- Citations by year
- 2026: 26 · 2025: 28 · 2024: 34 · 2023: 25 · 2022: 33 · 2021: 23 · 2020: 10
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Medicinal Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by-nc-nd)
- Funders
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (203.183/2018‐5)
- European Cooperation in Science and Technology (CA15135)
- Università di Bologna (RFO2019)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- Alzheimer's disease, polypharmacology, multi-target-directed ligands, combination therapy, codrugs, hybrid drugs, multi-target drug discovery, disease-modifying therapy, neurodegenerative diseases, drug attrition
- MeSH terms
- Alzheimer Disease, Pharmaceutical Preparations, Humans, Ligands, Drug Discovery, Polypharmacology
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