N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: strategies to eliminate reactive metabolites

  • Bioorg Med Chem Lett. 2013 Apr 15;23(8):2344-8. doi: 10.1016/j.bmcl.2013.02.066.
Sajiv K Nair  1 ,  Jean J Matthews ,  Stephan J Cripps ,  Hengmiao Cheng ,  Jacqui E Hoffman ,  Christopher Smith ,  Stanley Kupchinsky ,  Michael Siu ,  Wendy D Taylor ,  Yong Wang ,  Theodore O Johnson ,  Klaus R Dress ,  Martin P Edwards ,  Sue Zhou ,  Natilie A Hosea ,  Amy Lapaglia ,  Ping Kang ,  Arturo Castro ,  Jacques Ermolieff ,  Andrea Fanjul ,  Jennifer E Vogel ,  Paul Rejto ,  Deepak Dalvie
Affiliations
PMID: 23489629 DOI: 10.1016/j.bmcl.2013.02.066
Abstract

N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11β-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 11β-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.