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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).
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 Aug 23; Vol. 61 (16), pp. 7289-7313. Date of Electronic Publication: 2018 Aug 01. - Publication Year :
- 2018
-
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 (EC <subscript>50</subscript> <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.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics
Administration, Oral
Animals
Anti-HIV Agents pharmacokinetics
Benzoic Acid chemistry
Biological Availability
Chemistry Techniques, Synthetic
Chrysenes pharmacology
Dogs
Drug Design
Drug Stability
HIV-1 drug effects
HIV-1 genetics
Humans
Macaca fascicularis
Male
Mice, Inbred Strains
Mice, Knockout
Microsomes, Liver drug effects
Morpholines pharmacology
Polymorphism, Genetic
Rats, Sprague-Dawley
Triterpenes pharmacology
Anti-HIV Agents chemistry
Anti-HIV Agents pharmacology
Chrysenes chemistry
Morpholines chemistry
Structure-Activity Relationship
Triterpenes chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30067361
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b00854