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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)

2018; American Chemical Society; Volume: 61; Issue: 16 Linguagem: Inglês

10.1021/acs.jmedchem.8b00854

1520-4804

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 A. Easter, Brett R. Beno, Vinod Arora, Xiaohua 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,

Biochemical and Molecular Research

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.