2. Academic Validation
  3. 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

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

  • J Med Chem. 2022 Dec 8;65(23):15935-15966. 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
Affiliations

Affiliations

  • 1 Department of Small Molecule Drug Discovery, Bristol Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • 2 Department of Virology, Bristol Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • 3 Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
PMID: 36441509 DOI: 10.1021/acs.jmedchem.2c01618
Abstract

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.

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