1392312-45-6Relevant articles and documents
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)
Regueiro-Ren, Alicia,Swidorski, Jacob J.,Liu, Zheng,Chen, Yan,Sin, Ny,Sit, Sing-Yuen,Chen, Jie,Venables, Brian L.,Zhu, Juliang,Nowicka-Sans, Beata,Protack, Tricia,Lin, Zeyu,Terry, Brian,Samanta, Himadri,Zhang, Sharon,Li, Zhufang,Easter, John,Beno, Brett R.,Arora, Vinod,Huang, Xiaohua S.,Rahematpura, Sandhya,Parker, Dawn D.,Haskell, Roy,Santone, Kenneth S.,Cockett, Mark I.,Krystal, Mark,Meanwell, Nicholas A.,Jenkins, Susan,Hanumegowda, Umesh,Dicker, Ira B.
, p. 7289 - 7313 (2018/09/06)
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.
Synthesis of HIV-Maturation Inhibitor BMS-955176 from Betulin by an Enabling Oxidation Strategy
Ortiz, Adrian,Soumeillant, Maxime,Savage, Scott A.,Strotman, Neil A.,Haley, Matthew,Benkovics, Tamas,Nye, Jeffrey,Xu, Zhongmin,Tan, Yichen,Ayers, Sloan,Gao, Qi,Kiau, Susanne
, p. 4958 - 4963 (2017/05/12)
A concise and scalable second generation synthesis of HIV maturation inhibitor BMS-955176 is described. The synthesis is framed by an oxidation strategy highlighted by a CuI mediated aerobic oxidation of betulin, a highly selective PIFA mediated dehydrogenation of an oxime, and a subsequent Lossen rearrangement which occurs through a unique reaction mechanism for the installation of the C17 amino functionality. The synthetic route proceeds in 7 steps with 47% overall yield and begins from the abundant and inexpensive natural product betulin.
