Perhydroquinolylbenzamides as novel inhibitors of 11beta-hydroxysteroid dehydrogenase type 1.
J Med Chem
; 48(21): 6696-712, 2005 Oct 20.
Article
em En
| MEDLINE
| ID: mdl-16220986
ABSTRACT
High-throughput screening identified 5 as a weak inhibitor of 11beta-HSD1. Optimization of the structure led to a series of perhydroquinolylbenzamides, some with low nanomolar inhibitory potency. A tertiary benzamide is required for biological activity and substitution of the terminal benzamide with either electron-donating or -withdrawing groups is tolerated. The majority of the compounds show selectivity of >20 to >700-fold over 11beta-HSD2. Analogues which showed >50% inhibition of 11beta-HSD1 at 1 muM in an cellular assay were screened in an ADX mouse model. A maximal response of >70% reduction of liver corticosterone levels was observed for three compounds; 9m, 25 and 49.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzamidas
/
11-beta-Hidroxiesteroide Desidrogenase Tipo 1
/
Hidroquinonas
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article