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1.
J Med Chem ; 61(16): 7289-7313, 2018 08 23.
Article in English | MEDLINE | ID: mdl-30067361

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 (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.


Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Chrysenes/chemistry , Morpholines/chemistry , Structure-Activity Relationship , Triterpenes/chemistry , 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
2.
ACS Med Chem Lett ; 7(6): 568-72, 2016 Jun 09.
Article in English | MEDLINE | ID: mdl-27326328

ABSTRACT

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 (2), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen.

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