Discovery of pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase.
Bioorg Med Chem
; 15(16): 5576-89, 2007 Aug 15.
Article
en En
| MEDLINE
| ID: mdl-17560788
ABSTRACT
In an effort to identify hepatoselective inhibitors of HMG-CoA reductase, two series of pyrroles were synthesized and evaluated. Efforts were made to modify (3R,5R)-7-[3-(4-fluorophenyl)-1-isopropyl-4-phenyl-5-phenylcarbamoyl-1H-pyrrol-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt 30 in order to reduce its lipophilicity and therefore increase hepatoselectivity. Two strategies that were explored were replacement of the lipophilic 3-phenyl substituent with either a polar function (pyridyl series) or with lower alkyl substituents (lower alkyl series) and attachment of additional polar moieties at the 2-position of the pyrrole ring. One compound was identified to be both highly hepatoselective and active in vivo. We report the discovery, synthesis, and optimization of substituted pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase for reducing low density lipoprotein cholesterol (LDL-c) in the treatment of hypercholesterolemia.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirroles
/
Inhibidores de Hidroximetilglutaril-CoA Reductasas
/
Hidroximetilglutaril-CoA Reductasas
/
Hígado
Límite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2007
Tipo del documento:
Article
País de afiliación:
Estados Unidos