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The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2022 Sep 22; Vol. 65 (18), pp. 11927-11948. Date of Electronic Publication: 2022 Aug 31. - Publication Year :
- 2022
-
Abstract
- GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para -substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH <subscript>2</subscript> F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 65
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 36044257
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.2c00879