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

被引：27

作者：

Regueiro-Ren, Alicia ^{[1
,6
]}

Swidorski, Jacob J. ^{[1
]}

Liu, Zheng ^{[1
]}

Chen, Yan ^{[1
]}

Sin, Ny ^{[1
]}

Sit, Sing-Yuen ^{[1
]}

Chen, Jie ^{[1
]}

Venables, Brian L. ^{[1
]}

Zhu, Juliang ^{[2
]}

Nowicka-Sans, Beata ^{[3
]}

Protack, Tricia ^{[3
]}

Lin, Zeyu ^{[3
]}

Terry, Brian ^{[3
]}

Samanta, Himadri ^{[3
]}

Zhang, Sharon ^{[3
,7
]}

Li, Zhufang ^{[3
]}

Easter, John ^{[1
]}

Beno, Brett R. ^{[4
]}

Arora, Vinod ^{[5
]}

Huang, Xiaohua S. ^{[5
]}

Rahematpura, Sandhya ^{[5
]}

Parker, Dawn D. ^{[5
,7
]}

Haskell, Roy ^{[5
]}

Santone, Kenneth S. ^{[5
]}

Cocket, Mark I. ^{[3
,7
]}

Krystal, Mark ^{[3
,7
]}

Meanwell, Nicholas A. ^{[1
]}

Jenkins, Susan ^{[5
,7
]}

Hanumegowda, Umesh ^{[5
,7
]}

Dicker, Ira B. ^{[3
,7
]}

机构：

[1] Bristol Myers Squibb Res & Dev, Dept Discovery Chem & Mol Technol, 5 Res Pkwy, Wallingford, CT 06492 USA

[2] Bristol Myers Squibb Res & Dev, Dept Chem Synth, 5 Res Pkwy, Wallingford, CT 06492 USA

[3] Bristol Myers Squibb Res & Dev, Dept Virol, 5 Res Pkwy, Wallingford, CT 06492 USA

[4] Bristol Myers Squibb Res & Dev, Dept Mol Struct & Design, 5 Res Pkwy, Wallingford, CT 06492 USA

[5] Bristol Myers Squibb Res & Dev, Dept Pharmaceut Candidate Optimizat, 5 Res Pkwy, Wallingford, CT 06492 USA

[6] Bristol Myers Squibb, 350 Carter Rd,Room 126, Hopewell, NJ 08540 USA

[7] ViiV Healthcare, 36 East Ind Rd, Branford, CT 06405 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 16期

关键词：

IMMUNODEFICIENCY-VIRUS TYPE-1; IN-VITRO; PROTEASE INHIBITORS; ANTIRETROVIRAL THERAPY; ORGANIC-SYNTHESIS; DRUG DISCOVERY; P-GLYCOPROTEIN; BEVIRIMAT; SULFOXIMINES; BIOISOSTERES;

D O I：

10.1021/acs.jmedchem.8b00854

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：7289 / 7313

页数：25