American Chemical Society
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The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV‑1 Maturation

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posted on 2022-08-31, 16:06 authored by Alicia Regueiro-Ren, Sing-Yuen Sit, Yan Chen, Jie Chen, Jacob J. Swidorski, Zheng Liu, Brian L. Venables, Ny Sin, Richard A. Hartz, Tricia Protack, Zeyu Lin, Sharon Zhang, Zhufang Li, Dauh-Rurng Wu, Peng Li, James Kempson, Xiaoping Hou, Anuradha Gupta, Richard Rampulla, Arvind Mathur, Hyunsoo Park, Amy Sarjeant, Yulia Benitex, Sandhya Rahematpura, Dawn Parker, Thomas Phillips, Roy Haskell, Susan Jenkins, Kenneth S. Santone, Mark Cockett, Umesh Hanumegowda, Ira Dicker, Nicholas A. Meanwell, Mark Krystal
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.