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N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: Strategies to eliminate reactive metabolites
- Source :
-
Bioorganic & Medicinal Chemistry Letters . Apr2013, Vol. 23 Issue 8, p2344-2348. 5p. - Publication Year :
- 2013
-
Abstract
- 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. Display Omitted [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 0960894X
- Volume :
- 23
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Publication Type :
- Academic Journal
- Accession number :
- 86419739
- Full Text :
- https://doi.org/10.1016/j.bmcl.2013.02.066