Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
Bioorg Med Chem Lett
; 24(3): 954-62, 2014 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-24433859
ABSTRACT
The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15 nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99 nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Citocinas
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Inhibidores Enzimáticos
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Nicotinamida Fosforribosiltransferasa
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Amidas
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Aminopiridinas
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2014
Tipo del documento:
Article