Invention of VH-937, a Potent HIV‑1 Maturation\nInhibitor with the Potential for Infrequent Oral Dosing in Humans

Newer\ngeneration HIV-1 maturation inhibitors have proven to be\nviable antiretroviral agents in the clinic. VH3739937, (VH-937, <b>24</b>) is an advanced HIV-1 maturation inhibitor (MI) with a\n4-cyanopyridyl ether replacing the fluorine present in the previous\nlead MI GSK3640254 (GSK254, <b>3</b>). The introduction of aromatic\nmethylene ethers α to the carboxylic acid moiety significantly\nenhanced the antiviral profile, with additional inhibitory effects\nobserved toward the A364V mutation, the primary resistance mutation\nemerging in response to selective pressure by MIs. Structure–activity\noptimization led to the invention of VH-937, which combined the best\noverall antiviral profile with pharmacokinetic properties in animal\nmodels. These properties indicate the potential for infrequent dosing,\na finding confirmed in initial clinical studies in humans that suggests\nits potential as a once-weekly dosing agent.