N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11[beta]-hydroxysteroid dehydrogenase type 1: Strategies to eliminate reactive metabolites

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 8; pp. 2344 - 2348
• Main Authors: Nair, Sajiv K, Matthews, Jean J, Cripps, Stephan J, Cheng, Hengmiao, Hoffman, Jacqui E, Smith, Christopher, Kupchinsky, Stanley, Siu, Michael, Taylor, Wendy D, Wang, Yong, Johnson, Theodore O, Dress, Klaus R, Edwards, Martin P, Zhou, Sue, Hosea, Natilie A, LaPaglia, Amy, Kang, Ping, Castro, Arturo, Ermolieff, Jacques, Fanjul, Andrea, Vogel, Jennifer E, Rejto, Paul, Dalvie, Deepak
• Format: Journal Article
• Language: English
• Published: 15.04.2013
• ISSN: 0960-894X

N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11[beta]-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11[beta]-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.