2. Academic Validation
  3. Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176)

Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176)

  • J Med Chem. 2018 Aug 23;61(16):7289-7313. doi: 10.1021/acs.jmedchem.8b00854.
Alicia Regueiro-Ren,  Jacob J Swidorski,  Zheng Liu,  Yan Chen,  Ny Sin,  Sing-Yuen Sit,  Jie Chen,  Brian L Venables,  Juliang Zhu,  Beata Nowicka-Sans,  Tricia Protack,  Zeyu Lin,  Brian Terry,  Himadri Samanta,  Sharon Zhang,  Zhufang Li,  John Easter,  Brett R Beno,  Vinod Arora,  Xiaohua S Huang,  Sandhya Rahematpura,  Dawn D Parker,  Roy Haskell,  Kenneth S Santone,  Mark I Cockett,  Mark Krystal,  Nicholas A Meanwell,  Susan Jenkins,  Umesh Hanumegowda,  Ira B Dicker
PMID: 30067361 DOI: 10.1021/acs.jmedchem.8b00854
Abstract

GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.

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