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J Med Chem ; 48(21): 6696-712, 2005 Oct 20.
Article in English | 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.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Benzamides/chemical synthesis , Hydroquinones/chemical synthesis , Adrenalectomy , Animals , Benzamides/chemistry , Benzamides/pharmacology , Cells, Cultured , Corticosterone/metabolism , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Hydroquinones/chemistry , Hydroquinones/pharmacology , Liver/drug effects , Liver/metabolism , Male , Mice , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship
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