发明 VH-937，一种可用于人类非经常性口服的强效 HIV-1 成熟抑制剂。

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-10-17 eCollection Date: 2024-11-14 DOI:10.1021/acsmedchemlett.4c00419

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

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引用次数: 0

摘要

新一代 HIV-1 成熟抑制剂已被证明是临床上可行的抗逆转录病毒药物。VH3739937（VH-937，24）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之前的先导 MI GSK3640254（GSK254，3）中的氟。在羧酸分子中引入芳香亚甲基醚 α 能显著增强抗病毒效果，对 A364V 突变也有额外的抑制作用，A364V 突变是在 MIs 选择性压力下出现的主要抗性突变。通过结构-活性优化，我们发明了 VH-937，它结合了最佳的整体抗病毒特性和动物模型的药代动力学特性。这些特性表明，VH-937 具有不频繁给药的潜力，这一发现在人类的初步临床研究中得到了证实，表明它具有每周给药一次的潜力。

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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, 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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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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