The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation

  • J Med Chem. 2022 Sep 22;65(18):11927-11948. doi: 10.1021/acs.jmedchem.2c00879.
Alicia Regueiro-Ren  1 ,  Sing-Yuen Sit  2 ,  Yan Chen  2 ,  Jie Chen  2 ,  Jacob J Swidorski  2 ,  Zheng Liu  2 ,  Brian L Venables  2 ,  Ny Sin  2 ,  Richard A Hartz  2 ,  Tricia Protack  3 ,  Zeyu Lin  3 ,  Sharon Zhang  3 ,  Zhufang Li  3 ,  Dauh-Rurng Wu  4 ,  Peng Li  4 ,  James Kempson  4 ,  Xiaoping Hou  4 ,  Anuradha Gupta  5 ,  Richard Rampulla  4 ,  Arvind Mathur  4 ,  Hyunsoo Park  6 ,  Amy Sarjeant  6 ,  Yulia Benitex  7 ,  Sandhya Rahematpura  7 ,  Dawn Parker  7 ,  Thomas Phillips  7 ,  Roy Haskell  7 ,  Susan Jenkins  7 ,  Kenneth S Santone  7 ,  Mark Cockett  3 ,  Umesh Hanumegowda  7 ,  Ira Dicker  3 ,  Nicholas A Meanwell  1 ,  Mark Krystal  3
Affiliations
  • 1. Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Princeton, New Jersey08543, United States.
  • 2. Department of Discovery Chemistry, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • 3. Department of Virology, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • 4. Department of Discovery Synthesis, Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey08543, United States.
  • 5. Department of Discovery Synthesis; Bristol Myers Squibb Research and Early Development, Bangalore 560099, India.
  • 6. Bristol Myers Squibb Chemical and Synthetic Development, New Brunswick, New Jersey08901, United States.
  • 7. Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
PMID: 36044257 DOI: 10.1021/acs.jmedchem.2c00879
Abstract

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 para-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 CH2F 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.