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

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 ou...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-04, Vol.23 (8), p.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: Article
Language:English
Subjects:
11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors
11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism
11β-HSD
11β-Hydroxysteroid dehydrogenase
Aminopyridines - chemistry
Aminopyridines - pharmacokinetics
Aminopyridines - pharmacology
Bioactivation
Diabetes
glutathione
Glutathione - pharmacokinetics
Glutathione adduct
HEK293 Cells
Humans
Inhibitor
metabolites
PF-915275
pharmacokinetics
Reactive metabolite
risk-benefit analysis
Structure-Activity Relationship
structure-activity relationships
Sulfonamides - chemistry
Sulfonamides - pharmacokinetics
Sulfonamides - pharmacology
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Summary: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. [Display omitted]
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.02.066