Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Princeton, New Jersey08543, United States.
Department of Discovery Chemistry, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
J Med Chem. 2022 Sep 22;65(18):11927-11948. doi: 10.1021/acs.jmedchem.2c00879. Epub 2022 Aug 31.
GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the -substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CHF moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.
GSK3640254 是一种 HIV-1 成熟抑制剂（MI），对一系列临床相关的多态性变异体具有显著改善的抗病毒活性，对第二代 MI GSK3532795（BMS-955176）的敏感性降低。GSK3640254 与其前身的关键结构差异在于，用取代的环己-3-烯-1-羧酸取代了三萜核 C-3 位上连接的 -取代苯甲酸部分，该羧酸在与药效团羧酸的碳原子α处用 CHF 取代。这个结构元素提供了一个新的矢量，可以用来探索结构-活性关系（SARs），并导致具有改善的多态性覆盖的化合物，同时保留了药代动力学（PK）性质。讨论了 GSK3640254 的设计方法、合成路线的开发及其临床前特征。在对 HIV-1 感染受试者进行 7-10 天的给药后，GSK3640254 显示出剂量相关的 HIV-1 病毒载量降低，目前正在进行 IIb 期临床试验。
