Coppola, Gary, Kukkola, Paivi, Stanton, James, Neubert, Alan, Marcopulos, Nicholas, Bilci, Natalie, Wang, Hua, Tomaselli, Hollis, Tan, Jenny, Aicher, Thomas, Knorr, Douglas, Jeng, Arco, Dardik, Beatriz and Chatelain, Ricardo (2005) Perhydroquinolylbenzamides as novel inhibitors of 11beta-hydroxysteroid dehydrogenase type 1. Journal of Medicinal Chemistry, 48 (21). pp. 6696-6712. ISSN 0022-2623

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.

Item Type:	Article
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Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez...
Date Deposited:	14 Dec 2009 13:59
Last Modified:	14 Dec 2009 13:59
URI:	https://oak.novartis.com/id/eprint/494