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
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.