Discovery of BMS-955176, a Second Generation HIV‑1 Maturation Inhibitor with Broad Spectrum Antiviral Activity

HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (<b>2</b>), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen

Design, Synthesis, and SAR of C‑3 Benzoic Acid, C‑17 Triterpenoid Derivatives. Identification of the HIV‑1 Maturation Inhibitor 4‑((1<i>R</i>,3a<i>S</i>,5a<i>R</i>,5b<i>R</i>,7a<i>R</i>,11a<i>S</i>,11b<i>R</i>,13a<i>R</i>,13b<i>R</i>)‑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<i>H</i>‑cyclopenta[<i>a</i>]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176)

GSK3532795, formerly known as BMS-955176 (<b>1</b>), 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 (<b>3</b>) 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 <b>1</b>. These modifications ultimately enabled the discovery of <b>1</b> 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