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Perhydroquinolylbenzamides as novel inhibitors of 11beta-hydroxysteroid dehydrogenase type 1.

Coppola, Gary and Kukkola, Paivi and Stanton, James and Neubert, Alan and Marcopulos, Nicholas and Bilci, Natalie and Wang, Hua and Tomaselli, Hollis and Tan, Jenny and Aicher, Thomas and Knorr, Douglas and Jeng, Arco and 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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Date Deposited: 14 Dec 2009 13:59
Last Modified: 14 Dec 2009 13:59
URI: https://oak.novartis.com/id/eprint/494

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