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

Newer generation HIV-1 maturation inhibitors have proven to be viable antiretroviral agents in the clinic. VH3739937, (VH-937, <b>24</b>) is an advanced HIV-1 maturation inhibitor (MI) with a 4-cyanopyridyl ether replacing the fluorine present in the previous lead MI GSK3640254 (GSK254, <b>3</b>). 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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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2024-10-17
DOI
https://doi.org/10.1021/acsmedchemlett.4c00419
Citations
6
Primary Topic
HIV/AIDS drug development and treatment
Type
article
Field-Weighted Citation Impact
2.33

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article

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

Zhufang Li, Jacob J. Swidorski, Paul Falk, Alicia Regueiro‐Ren et al.
6 citations
ACS Medicinal Chemistry Letters
HIV/AIDS drug development and treatment
2.33
article

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

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

Abstract

Newer generation HIV-1 maturation inhibitors have proven to be viable antiretroviral agents in the clinic. VH3739937, (VH-937, <b>24</b>) is an advanced HIV-1 maturation inhibitor (MI) with a 4-cyanopyridyl ether replacing the fluorine present in the previous lead MI GSK3640254 (GSK254, <b>3</b>). 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.

ACS Medicinal Chemistry LettersVol. 15(11)
Bristol-Myers Squibb (United States) (US)
Bristol-Myers Squibb, ViiV Healthcare
Good health and well-being
Openalex Percentile: Top 11%
HIV/AIDS drug development and treatment
2.33
DOIOpen Access PDFOpenAlex
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