Maximizing lipophilic efficiency: the use of Free-Wilson analysis in the design of inhibitors of acetyl-CoA carboxylase.
J Med Chem
; 55(2): 935-42, 2012 Jan 26.
Article
en En
| MEDLINE
| ID: mdl-22148323
ABSTRACT
This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Acetil-CoA Carboxilasa
/
Pirazoles
/
Compuestos de Espiro
/
Bencimidazoles
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Hipoglucemiantes
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Indazoles
/
Indoles
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos