Perhydroquinolylbenzamides as Novel Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1
| Autor: | Nicholas Marcopulos, Gary M. Coppola, Beatriz Dardik, Paivi J. Kukkola, Jenny Tan, Hua Wang, Ricardo E. Chatelain, James L. Stanton, Alan D. Neubert, Natalie A. Bilci, Thomas D. Aicher, Arco Y. Jeng, Hollis C. Tomaselli, Douglas C. Knorr |
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| Rok vydání: | 2005 |
| Předmět: |
Male
medicine.drug_class Carboxamide Pharmacology Chemical synthesis Rats Sprague-Dawley Mice Structure-Activity Relationship chemistry.chemical_compound 11β-hydroxysteroid dehydrogenase type 1 11-beta-Hydroxysteroid Dehydrogenase Type 1 Drug Discovery medicine Animals Humans Benzamide Cells Cultured chemistry.chemical_classification biology Adrenalectomy Stereoisomerism Biological activity In vitro Hydroquinones Rats Enzyme Liver chemistry Biochemistry Enzyme inhibitor Benzamides Hepatocytes biology.protein Molecular Medicine Corticosterone hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Medicinal Chemistry. 48:6696-6712 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm058228q |
| Popis: | 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 of20 to700-fold over 11beta-HSD2. Analogues which showed50% inhibition of 11beta-HSD1 at 1 muM in an cellular assay were screened in an ADX mouse model. A maximal response of70% reduction of liver corticosterone levels was observed for three compounds; 9m, 25 and 49. |
| Databáze: | OpenAIRE |
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