Synthesis and structure-activity relationship of 2-adamantylmethyl tetrazoles as potent and selective inhibitors of human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1).
Bioorg Med Chem Lett
; 24(2): 654-60, 2014 Jan 15.
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| MEDLINE
| ID: mdl-24360604
ABSTRACT
A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11ß-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11ß-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11ß-HSD1 with a favorable development profile.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Tetrazoles
/
Adamantano
/
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2014
Tipo del documento:
Article