Synthesis, Structure–Activity Relationships, and In Vivo Evaluation of Novel C-17 Amine Derivatives Based on GSK3640254 as HIV-1 Maturation Inhibitors with Broad Spectrum Activity,Journal of Medicinal Chemistry

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Synthesis, Structure–Activity Relationships, and In Vivo Evaluation of Novel C-17 Amine Derivatives Based on GSK3640254 as HIV-1 Maturation Inhibitors with Broad Spectrum Activity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-28 , DOI: 10.1021/acs.jmedchem.2c01618
Richard A Hartz ₁ , Li Xu ₁ , Sing-Yuen Sit ₁ , Jie Chen ₁ , Brian L Venables ₁ , Zeyu Lin ₂ , Sharon Zhang ₂ , Zhufang Li ₂ , Dawn Parker ₃ , Tara S Simmons ₃ , Susan Jenkins ₃ , Umesh M Hanumegowda ₃ , Ira Dicker ₂ , Mark Krystal ₂ , Nicholas A Meanwell ₁ , Alicia Regueiro-Ren ₁

Affiliation

An investigation of the structure–activity relationships of a series of HIV-1 maturation inhibitors (MIs) based on GSK3640254 (4) was conducted by incorporating novel C-17 amine substituents to reduce the overall basicity of the resultant analogues. We found that replacement of the distal amine on the C-17 sidechain present in 4 with a tertiary alcohol in combination with either a heterocyclic ring system or a cyclohexyl ring substituted with polar groups provided potent wild-type HIV-1 MIs that also retained excellent potency against a T332S/V362I/prR41G variant, a laboratory strain that served as a surrogate to assess HIV-1 polymorphic virus coverage. Compound 26 exhibited broad-spectrum HIV-1 activity against an expanded panel of clinically relevant Gag polymorphic viruses and had the most desirable overall profile in this series of compounds. In pharmacokinetic studies, 26 had low clearance and exhibited 24 and 31% oral bioavailability in rats and dogs, respectively.

中文翻译：

基于 GSK3640254 作为具有广谱活性的 HIV-1 成熟抑制剂的新型 C-17 胺衍生物的合成、构效关系和体内评价

对基于 GSK3640254 ( 4 ) 的一系列 HIV-1 成熟抑制剂 (MI) 的构效关系进行了研究，方法是掺入新型 C-17 胺取代基以降低所得类似物的整体碱度。我们发现，将4中存在的 C-17 侧链上的远端胺替换为叔醇，结合杂环系统或被极性基团取代的环己基环，可提供有效的野生型 HIV-1 MI，同时保留了出色的性能对 T332S/V362I/prR41G 变体的效力，这是一种实验室菌株，可作为评估 HIV-1 多态性病毒覆盖率的替代物。化合物26表现出针对临床相关 Gag 多态性病毒的扩展组的广谱 HIV-1 活性，并且在这一系列化合物中具有最理想的总体特征。在药代动力学研究中，26种药物的清除率较低，在大鼠和狗中的口服生物利用度分别为 24% 和 31%。

更新日期：2022-11-28

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