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Why Are the Majority of Active Compounds in the CNS Domain Natural Products? A Critical Analysis

Bharate, Sonali S., Mignani, Serge, Vishwakarma, Ram A.·2018·Journal of Medicinal Chemistry
DOI 10.1021/acs.jmedchem.7b01922
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Abstract

Small-molecule natural products (NPs) have a long and successful track record of providing first-in-class drugs and pharmacophore (scaffolds) in all therapeutic areas, serving as a bridge between modern and traditional medicine. This trajectory has been remarkably successful in three key areas of modern therapeutics: cancers, infections, and CNS diseases. Beginning with the discovery of morphine 200 years ago, natural products have remained the primary source of new drugs/scaffolds for CNS diseases. In this perspective, we address the question: why are the majority of active compounds in the CNS domain natural products? Our analysis indicates that ∼84% approved drugs for CNS diseases are NPs or NP-inspired, and interestingly, 20 natural products provided more than 400 clinically approved CNS drugs. We have discussed unique physicochemical properties of NPs and NP-inspired vis-à-vis synthetic drugs, isoform selectivity, and evolutionary relationship, providing a rationale for increasing focus on natural product driven discovery for next-generation drugs for neurodegenerative diseases.

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  • TAC possesses a low molecular weight (<400 Da) and lipophilicity that favor drug uptake across all tissues, including the CNS.

    “TAC possesses a low molecular weight (<400 Da) and lipophilicity that favor drug uptake across all tissues, including the CNS.45”

    From TERT activation targets DNA methylation and multiple aging hallmarks (2024) · cites this paper as [45]

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Metadata

Authors
Bharate, S. S., Mignani, S., & Vishwakarma, R. A.
Affiliations
  • Preformulation Laboratory, PK−PD Toxicology and Formulation Division, CSIR—Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
  • UMR 860, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologique, Université Paris Descartes, PRES Sorbonne Paris Cité, CNRS, 45 rue des Saints Pères, 75006 Paris, France
  • Medicinal Chemistry Division, CSIR—Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2018-07-10
Volume
61
Issue
23
Pages
10345-10374
ISSN
  • 0022-2623
  • 1520-4804
DOI
10.1021/acs.jmedchem.7b01922
Cited by
102
References
7
Language
en
Funders
Department of Biotechnology , Ministry of Science and Technology (GAP-2158)

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