Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.
Bioorg Med Chem Lett
; 26(8): 1925-30, 2016 Apr 15.
Article
en En
| MEDLINE
| ID: mdl-26988305
ABSTRACT
We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Triterpenos
/
Benzoatos
/
VIH
/
Fármacos Anti-VIH
/
Amidas
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2016
Tipo del documento:
Article