A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

R207910 is a pure enantiomer with two chiral centers.

“The most active compound of the class, R207910, is a pure enantiomer with two chiral centers.”

May combine two claims.

No accumulation of R207910 was observed after five daily oral doses, indicating that slow redistribution from tissues contributed to the relatively long half-lives in plasma.

“No accumulation of R207910 was observed after five daily oral doses, indicating that slow redistribution from tissues contributed to the relatively long half-lives in plasma.”

May combine two claims.

In the second study, the good tolerability was maintained; only one subject withdrew from the study, because of a urinary tract infection (unrelated to R207910) after seven doses at 150 mg/day.

“In the second study, the good tolerability was maintained; only one subject withdrew from the study, because of a urinary tract infection (unrelated to R207910) after seven doses at 150 mg/day.”

May combine two claims.

When added to the first-line triple TB therapy combination RHZ, 25 mg/kg R207910 (J) increased the drop in bacterial load in the lungs by 2 log10 after 1 month of therapy compared with standard RHZ treatment regimen, and a further 1 log10 drop after 2 months.

“When added to the first-line triple TB therapy combination RHZ, 25 mg/kg R207910 (J) increased the drop in bacterial load in the lungs by 2 log 10 after 1 month of therapy compared with standard RHZ treatment regimen, and a further 1 log 10 drop after 2 months.”

May combine two claims.

Maximum plasma concentrations (Cmax) of 0.40-0.54 μg/ml with a single 6.25 mg/kg dose were achieved within 1 hour and 1.1-1.3 μg/ml with a 25 mg/kg dose within 2-4 hours.

“Maximum plasma concentrations (C max ) of 0.40-0.54µg/ml with a single 6.25 mg/kg/dose were achieved within 1 hour and 1.1-1.3µg/ml with a 25 mg/kg/dose within 2-4 hours.”

May combine two claims.

The majority of adverse events reported were considered possibly related to the study medication-placebo (seven of 18 subjects) or R207910 (20 of 36 subjects).

“The majority of adverse events reported (supporting online text), were considered possibly related to the study medication-placebo (seven of 18 subjects) or R207910 (20 of 36 subjects).”

May combine two claims.

The AUC showed a better correlation with the dose than Cmax, reflecting limitations in rate of absorption at higher dosing regimens, as confirmed in a single-dose pharmacokinetic study comparing Cmax and AUC after 6.25, 25 and 100 mg/kg.

“The AUC showed a better correlation with the dose than C max , reflecting limitations in rate of absorption at higher dosing regimens, as confirmed in a single-dose pharmacokinetic study comparing C max and AUC after 6.25, 25 and 100 mg/kg.”

May combine two claims.

This anti-mycobacterial-specific spectrum differs from that of isoniazid, which has very poor activity against MAC.

“This anti-mycobacterial-specific spectrum differs from that of isoniazid, which has very poor activity against MAC.”

May combine two claims.

In studies using oral treatment of R207910 for 5 days per week for 4 weeks, starting the day after inoculation, the minimal dose of R207910 that prevented mortality in nonestablished infection was 1.5 mg/kg, and the minimal effective dose (MED) preventing gross lung lesions was 6.5 mg/kg.

“In studies using oral treatment of R207910 for 5 days per week for 4 weeks, starting the day after inoculation, the minimal dose of R207910 that prevented mortality in nonestablished infection was 1.5 mg/kg, and the minimal effective dose (MED) preventing gross lung lesions was 6.5 mg/kg.”

May combine two claims.

Exposure of M. tuberculosis in log-phase growth to concentrations of R207910 at 10-fold MIC resulted in a 3 log10 reduction in bacterial counts after 12 days, indicating bactericidal activity in vitro.

“Exposure of M. tuberculosis in log-phase growth to concentrations of R207910 at 10-fold MIC resulted in a 3 log 10 reduction in bacterial counts after 12 days, indicating that R207910 has bactericidal activity in vitro (table S2).”

May combine two claims.

Complementation studies have verified that the mutant atpE gene is responsible for resistance to R207910, implying that the atpE gene product is the target of R207910 in mycobacteria.

“Complementation studies have verified that the mutant atpE gene is responsible for resistance to R207910, implying that the atpE gene product is the target of R207910 in mycobacteria.”

May combine two claims.

The range of MICs for M. tuberculosis H37Rv and six fully antibiotic susceptible isolates was 0.03-0.120 μg/ml, versus 0.500 μg/ml for rifampin and 0.120 μg/ml for isoniazid.

“The range of MICs for the international reference strain M. tuberculosis H37Rv and six fully antibiotic susceptible isolates was 0.03-0.120µg/ml (Table 1), versus 0.500 µg/ml for rifampin and 0.120 µg/ml for isoniazid (results not shown).”

May combine two claims.

All 30 isolates of MDR-TB tested were susceptible to 0.100 μg/ml of R207910, and 17 (57%) were susceptible to 0.010 μg/ml.

“All 30 isolates of MDR-TB tested were susceptible to 0.100 µg/ml of R207910, and 17 (57%) were susceptible to 0.010 µg/ml of R207910 (Table 2).”

May combine two claims.

R207910 is well absorbed after single oral administration, and the peak concentration was reached at 5 hours (median value) post-dose.

“Pharmacokinetic results from the single-ascending-dose study suggested that R207910 is well absorbed after single oral administration, and the peak concentration was reached at 5 hours (median value) post-dose.”

May combine two claims.

R207910 had much higher MICs for Corynebacterium and Helicobacter pylori (MIC 4.0 μg/ml), and especially for other organisms such as Gram-positive Nocardia, Streptococcus pneumoniae, Staphylococcus aureus and Enterococcus faecalis, or Gram-negative Escherichia coli and Haemophilus influenzae.

“R207910 had much higher MICs for Corynebacterium and Helicobacter pylori (MIC 4.0 µg/ml), and especially for other organisms such as Gram-positive Nocardia, Streptococcus pneumoniae, Staphylococcus aureus and Enterococcus faecalis, or Gram-negative Escherichia coli and Haemophilus influenzae (table S1).”

May combine two claims.

Half-lives ranged from 43.7 to 64 hours in plasma and 28.1 to 92 hours in tissues.

“Half-lives ranged from 43.7 to 64 hours in plasma and 28.1 to 92 hours in tissues (table S4).”

May combine two claims.

Substitution of drugs in the WHO first-line TB treatment regimen with R207910 accelerates bactericidal activity, leading to complete culture conversion after 2 months in some combinations.

“Substitution of drugs included in the World Health Organization's firstline tuberculosis treatment regimen (rifampin, isoniazid and pyrazinamide) with R207910 accelerates bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations.”

May combine two claims.

The DARQ R207910 is a member of a new chemical class of anti-mycobacterial agents and has an MIC equal to or lower than that of reference compounds.

“The DARQ R207910 is a member of a new chemical class of anti-mycobacterial agents and has an MIC equal to or lower than that of reference compounds.”

May combine two claims.

A single dose of 50 mg/kg R207910 in the non-established infection murine model of TB resulted in a bacteriostatic effect (0.5 log10 drop in bacterial count in the lungs), which lasted for 8 days-a similar effect to that of rifapentine (10 mg/kg).

“A single dose of 50 mg/kg R207910 in the non-established infection murine model of TB infection resulted in a bacteriostatic effect (0.5 log 10 drop in bacterial count in the lungs), which lasted for 8 days-a similar effect to that of rifapentine (10 mg/kg) (Fig. 3B).”

May combine two claims.

In established infection (treatment beginning 12-14 days after inoculation when bacterial load was 5.94 log10 CFU), 25 mg/kg R207910 as monotherapy was at least as active as the triple combination therapy (rifampin + isoniazid + pyrazinamide), and more active than rifampin alone.

“In established infection (treatment beginning 12-14 days after inoculation when bacterial load was 5.94 log 10 CFU), 25 mg/kg R207910 as monotherapy was at least as active as the triple combination therapy (rifampin [R] + isoniazid [H] + pyrazinamide [Z]), and more active than rifampin alone (Fig. 4B).”

May combine two claims.

R207910 is a diarylquinoline that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro, with MIC 0.06 μg/ml.

“We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (MIC 0.06 µg/ml).”

May combine two claims.

The mean AUC0-24h values were 7.91, 24 and 52 μg/hour/ml at steady state, corresponding to average concentrations of 0.33, 1.0 and 2.2 μg/ml across a dosing interval, with 50, 150 and 400 mg/day, respectively.

“The mean AUC 0-24h values were 7.91, 24 and 52 µg/hour/ml at steady state, corresponding to average concentrations of 0.33, 1.0 and 2.2 µg/ml across a dosing interval, with 50, 150 and 400 mg/day, respectively.”

May combine two claims.

The pharmacokinetics of R207910 were linear up to the highest dose tested (700 mg); both Cmax and AUC increased proportionally with the administered dose.

“The pharmacokinetics of R207910 were linear up to the highest dose tested (700 mg); both C max and AUC increased proportionally with the administered dose.”

May combine two claims.

The two point mutations identified (D32V for M. smegmatis and A63P for M. tuberculosis) are both in the membrane-spanning domain region of the protein.

“The two point mutations identified (D32V for M. smegmatis and A63P for M. tuberculosis) are both in the membrane-spanning domain region of the protein.”

May combine two claims.

AUCs ranged from 5.0 to 5.9 μg/hour/ml with a 6.25 mg/kg dose and 18.5 to 19.4 μg/hour/ml with a 25 mg/kg dose.

“Areas under the concentration-time curve (AUCs) ranged from 5.0 to 5.9 µg/hour/ml with a 6.25 mg/kg/dose and 18.5 to 19.4 µg/hour/ml with a 25 mg/kg/dose (table S4).”

May combine two claims.

The proportion of resistant mutants that emerged was 5 x 10^-7 and 2 x 10^-8 at four-fold MIC, and 5 x 10^-8 and 1 x 10^-8 at eight-fold MIC for M. tuberculosis and M. smegmatis, respectively.

“From selection experiments, the proportion of resistant mutants that emerged was 5 x 10 -7 and 2 x 10 -8 at four-fold MIC, and 5 x 10 -8 and 1 x 10 -8 at eight-fold MIC for M. tuberculosis and M. smegmatis, respectively (8).”

• cites [8] 8. Details of materials and methods and supporting online text are available as supporting material on Science Online.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Substitution of each of the three first-line drugs with R207910 resulted in a dramatic increase in potency, leading to complete culture conversion of the lungs in some animals after only 2 months of treatment.

“Substitution of each of the three first-line drugs with R207910 resulted in a dramatic increase in potency, leading to complete culture conversion of the lungs in some animals after only 2 months of treatment.”

May combine two claims.

R207910 has potent early bactericidal activity in the nonestablished murine TB model, matching or exceeding that of isoniazid, which is consistent with in vitro observations pointing to a bactericidal activity.

“R207910 has potent early bactericidal activity in the nonestablished murine TB model, matching or exceeding that of isoniazid (Fig. 4A), which is consistent with in vitro observations pointing to a bactericidal activity.”

May combine two claims.

The bactericidal potency seen upon administration of a single dose of 100 mg/kg R207910 in vivo was similar to the effect seen upon continuous exposure of cultures to 0.6 μg/ml (or 10-fold the median MIC of the H37Rv strain) in vitro, giving a first indication of the pharmacodynamics of R207910.

“Interestingly, the bactericidal potency seen upon administration of a single dose of 100 mg/kg R207910 in vivo was similar to the effect seen upon continuous exposure of cultures to 0.6 µg/ml (or 10-fold the median MIC of the H37Rv strain) in vitro, giving a first indication of the pharmacodynamics of R207910.”

May combine two claims.

The minimal bactericidal dose was very close to the MED, a finding confirming time-dependent, rather than concentration-dependent, activity of R207910 in vitro.

“Thus, the minimal bactericidal dose was very close to the MED, a finding confirming timedependent, rather than concentration-dependent, activity of R207910 in vitro.”

May combine two claims.

Data suggest that maintaining average plasma levels of 0.3 μg/ml/day across a dosing interval, which is achieved with a 100 mg/kg/week dose, is necessary to achieve optimal effect of monotherapy in mice infected with strain H37Rv.

“Data suggest that maintaining average plasma levels of 0.3 µg/ml/day across a dosing interval, which is achieved with a 100 mg/kg/week dose, is necessary to achieve optimal effect of monotherapy in mice infected with strain H37Rv.”

May combine two claims.

The killing effect was not increased by higher concentrations of R207910, suggesting time-dependent rather than concentration-dependent killing.

“The killing effect was not increased by higher concentrations of the compound, suggesting the killing was time-dependent rather than concentration-dependent.”

Classified as probably not a substantial claim. May combine two claims.

Current first-line anti-TB drug regimens can achieve more than 99% efficacy, but this is often reduced because of drug resistance.

“Although current first-line anti-TB drug regimens can achieve more than 99% efficacy, this is often reduced because of drug resistance (5).”

• cites [5] 5. R. J. O'Brien, P. P. Nunn, Am. J. Respir. Crit. Care Med. 163, 1055 (2001).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Structurally and mechanistically, DARQs are very different from fluoroquinolones and other quinoline classes, including mefloquine and its analogs.

“Structurally and mechanistically, DARQs are very different from both fluoroquinolones (including methoxyquinolones) and other quinoline classes, including mefloquine and its analogs 4-methylquinolines and 4quinolylhydrazones (9-13).”

• cites [9] 9. R. Jain, B. Vaitilingam, A. Nayyar, P. B. Palde, Bioorg. Med. Chem. Lett. 13, 1051 (2003).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [10] 10. C. M. Kunin, W. Y. Ellis, Antimicrob. Agents Chemother. 44, 848 (2000).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [11] 11. M. R. Barbachyn, S. J. Brickner, Patent (International Publication Number: WO 93/09103, International Publication Date: 13 May, 1993, International Application Number: PCT/US92/08267, International Filing Date: 1992).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [12] 12. L. Savini, L. Chiasserini, A. Gaeta, C. Pellerano, Bioorg. Med. Chem. 10, 2193 (2002). / www.sciencexpress.org /9 December 2004 / Page 4/ 10.1126/science.1106753Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [13] 13. S. Vangapandu, M. Jain, R. Jain, S. Kaur, P. P. Singh, Bioorg. Med. Chem. 12, 2501 (2004).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

The long half-lives and consequently prolonged exposure are important factors determining the duration of activity in vivo and provide a rationale for less frequent dosing regimens.

“The long half-lives and consequently prolonged exposure are important factors determining the duration of activity in vivo and provide a rationale for less frequent dosing regimens.”

May combine two claims.

A comparison of the sequences of ATP synthases of different bacteria and of eukaryotic ATP synthase provides a rationale for the specificity of the antibacterial spectrum and, to a lesser extent, the safety profile of R207910.

“A comparison of the sequences of ATP synthases of different bacteria and of eukaryotic ATP synthase provides a rationale for the specificity of the antibacterial spectrum and, to a lesser extent, the safety profile of R207910.”

May combine two claims.

The distinct target of R207910 means that there is no cross-resistance with existing anti-TB drugs, and our studies verified it is as effective against MDR strains as it is against fully antibiotic-susceptible strains.

“Furthermore, the distinct target of R207910 means that there is no crossresistance with existing anti-TB drugs, and our studies verified it is as effective against MDR strains as it is against fully antibiotic-susceptible strains.”

May combine two claims.

Inhibition of ATP synthase function may lead to ATP depletion and imbalance in pH homeostasis, both contributing to decreased survival.

“Inhibition of ATP synthase function may lead to ATP depletion and imbalance in pH homeostasis, both contributing to decreased survival (15,16).”

• cites [15] 15. M. Rao, T. L. Streur, F. E. Aldwell, G. M. Cook, Microbiology 147, 1017 (2001).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [16] 16. G. Deckers-Hebestreit, K. Altendorf, Annu. Rev. Microbiol. 50, 791 (1996).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

These attributes are valuable for treatment of chronic infections and may also be important for the development of simpler dosing regimens.

“These are all attributes that are valuable for treatment of chronic infections and they may also be important for the development of simpler dosing regimens.”

May combine two claims.

The extent of bacterial load, the most effective drug combinations and treatment duration needed for sterilization are all similar in mice and humans.

“The extent of bacterial load, the most effective drug combinations and treatment duration needed for sterilization are all similar in mice and humans (17).”

• cites [17] 17. E. L. Nuermberger et al., Am. J. Respir. Crit. Care Med. 169, 421 (2004).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.