Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
J Med Chem
; 56(12): 4921-37, 2013 Jun 27.
Article
em En
| MEDLINE
| ID: mdl-23617784
ABSTRACT
Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 µM; A2780 IC50 = 0.032 µM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ureia
/
Inibidores Enzimáticos
/
Nicotinamida Fosforribosiltransferase
/
Descoberta de Drogas
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2013
Tipo de documento:
Article