RESUMO
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.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Crisenos/química , Morfolinas/química , Relação Estrutura-Atividade , Triterpenos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Administração Oral , Animais , Fármacos Anti-HIV/farmacocinética , Ácido Benzoico/química , Disponibilidade Biológica , Técnicas de Química Sintética , Crisenos/farmacologia , Cães , Desenho de Fármacos , Estabilidade de Medicamentos , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Macaca fascicularis , Masculino , Camundongos Endogâmicos , Camundongos Knockout , Microssomos Hepáticos/efeitos dos fármacos , Morfolinas/farmacologia , Polimorfismo Genético , Ratos Sprague-Dawley , Triterpenos/farmacologiaRESUMO
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.