Sit Sing-Yuen, Chen Yan, Chen Jie, Venables Brian L, Swidorski Jacob J, Xu Li, Sin Ny, Hartz Richard A, Lin Zeyu, Zhang Sharon, Li Zhufang, Wu Dauh-Rurng, Li Peng, Kempson James, Hou Xiaoping, Shanmugam Yoganand, Parker Dawn, Jenkins Susan, Simmermacher Jean, Falk Paul, McAuliffe Brian, Cockett Mark, Hanumegowda Umesh, Dicker Ira, Krystal Mark, Meanwell Nicholas A, Regueiro-Ren Alicia
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.
Bristol-Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08543, United States.
ACS Med Chem Lett. 2024 Oct 17;15(11):1997-2004. doi: 10.1021/acsmedchemlett.4c00419. eCollection 2024 Nov 14.
Newer generation HIV-1 maturation inhibitors have proven to be viable antiretroviral agents in the clinic. VH3739937, (VH-937, ) is an advanced HIV-1 maturation inhibitor (MI) with a 4-cyanopyridyl ether replacing the fluorine present in the previous lead MI GSK3640254 (GSK254, ). 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.
新一代HIV-1成熟抑制剂已被证明在临床上是可行的抗逆转录病毒药物。VH3739937（VH-937）是一种先进的HIV-1成熟抑制剂（MI），其4-氰基吡啶基醚取代了先前先导MI GSK3640254（GSK254）中的氟。在羧酸部分的α位引入芳基亚甲基醚显著增强了抗病毒谱，对A364V突变（这是MI选择性压力下出现的主要耐药突变）有额外的抑制作用。结构活性优化导致了VH-937的发明，它在动物模型中结合了最佳的整体抗病毒谱和药代动力学特性。这些特性表明其具有不频繁给药的潜力，这一发现已在人体初步临床研究中得到证实，表明它有作为每周一次给药药物的潜力。
