Hepatoselectivity of statins: design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors.
Bioorg Med Chem Lett
; 18(3): 1151-6, 2008 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-18155906
ABSTRACT
4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Münchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.
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Base de dados:
MEDLINE
Assunto principal:
Pirróis
/
Sulfonamidas
/
Inibidores de Hidroximetilglutaril-CoA Redutases
/
Células Musculares
Limite:
Animals
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article