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

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

Affiliation

  • 1 Medicinal Chemistry, Pfizer Global R&D, San Diego, CA 92121, USA. sajiv.k.nair@pfizer.com
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.

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