The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation

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 CH2F moiety at the carbon atom alpha- 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.

Automated summary

GSK3640254 is an HIV-1 maturation inhibitor with significantly improved antiviral activity against clinically relevant polymorphic variants and reduced sensitivity towards the second-generation inhibitor GSK3532795. The replacement of the para-substituted benzoic acid moiety with a cyclohex-3-ene-1-carboxylic acid substituted with a CH2F moiety led to improved polymorphic coverage and preserved pharmacokinetic properties. GSK3640254 is currently undergoing phase IIb clinical trials and has shown dose-related reduction in HIV-1 viral load.