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

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Newer generation HIV-1 maturation inhibitors have proven to be viable antiretroviral agents in the clinic. VH3739937, (VH-937, 24 ) is an advanced HIV-1 maturation inhibitor (MI) with a 4-cyanopyridyl ether replacing the fluorine present in the previous lead MI GSK3640254 (GSK254, 3 ). The introduction of aromatic methylene ethers α to the carboxylic acid moiety significantly enhanced the antiviral profile, with additional inhibitory effects observed toward the A364V mutation, the primary resistance mutation emerging in response to selective pressure by MIs. Structure–activity optimization led to the invention of VH-937, which combined the best overall antiviral profile with pharmacokinetic properties in animal models. These properties indicate the potential for infrequent dosing, a finding confirmed in initial clinical studies in humans that suggests its potential as a once-weekly dosing agent.

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