Synthesis, X-ray analysis, and biological evaluation of a new class of stereopure lactam-based HIV-1 protease inhibitors.
J Med Chem
; 55(6): 2724-36, 2012 Mar 22.
Article
em En
| MEDLINE
| ID: mdl-22376008
ABSTRACT
In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure ß-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K(i) of 2.1 nM and an EC(50) of 0.64 µM. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K(i) = 0.8 nM, EC(50) = 0.04 µM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Protease de HIV
/
Inibidores da Protease de HIV
/
Lactamas
Limite:
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article