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

Sing-Yuen Sit; Yan Chen; Jie Chen; Brian L Venables; Jacob J Swidorski; Li Xu; Ny Sin; Richard A Hartz; Zeyu Lin; Sharon Zhang; Zhufang Li; Dauh-Rurng Wu; Peng Li; James Kempson; Xiaoping Hou; Yoganand Shanmugam; Dawn Parker; Susan Jenkins; Jean Simmermacher; Paul Falk; Brian McAuliffe; Mark Cockett; Umesh Hanumegowda; Ira Dicker; Mark Krystal; Nicholas A Meanwell; Alicia Regueiro-Ren

doi:10.1021/acsmedchemlett.4c00419

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

ACS Med Chem Lett. 2024 Oct 17;15(11):1997-2004. doi: 10.1021/acsmedchemlett.4c00419. eCollection 2024 Nov 14.

Authors

Sing-Yuen Sit¹, Yan Chen¹, Jie Chen¹, Brian L Venables¹, Jacob J Swidorski¹, Li Xu^{1

2}, Ny Sin¹, Richard A Hartz^{1

2}, Zeyu Lin¹, Sharon Zhang¹, Zhufang Li¹, Dauh-Rurng Wu^{1

2}, Peng Li¹, James Kempson^{1

2}, Xiaoping Hou^{1

2}, Yoganand Shanmugam¹, Dawn Parker^{1

3}, Susan Jenkins^{1

3}, Jean Simmermacher^{1

3}, Paul Falk^{1

3}, Brian McAuliffe^{1

3}, Mark Cockett¹, Umesh Hanumegowda^{1

3}, Ira Dicker¹, Mark Krystal^{1

3}, Nicholas A Meanwell^{1

2}, Alicia Regueiro-Ren^{1

2}

Affiliations

¹ Departments of Discovery Chemistry, Virology, Pharmaceutical Candidate Optimization, and Discovery Synthesis, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
² Bristol-Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08543, United States.
³ ViiV Healthcare, 36 East Industrial Road, Branford, Connecticut 06405, United States.

PMID: 39563829
PMCID: PMC11571082 (available on 2025-11-14)
DOI: 10.1021/acsmedchemlett.4c00419

Abstract

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.