title: N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: strategies to eliminate reactive metabolites.
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.
authors.affiliation: Medicinal Chemistry, Pfizer Global R&D, San Diego, CA 92121, USA. sajiv.k.nair@pfizer.com
authors.forename: Sajiv K
authors.initials: SK
authors.lastname: Nair
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Matthews
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Cripps
authors.forename: Hengmiao
authors.initials: H
authors.lastname: Cheng
authors.forename: Jacqui E
authors.initials: JE
authors.lastname: Hoffman
authors.forename: Christopher
authors.initials: C
authors.lastname: Smith
authors.forename: Stanley
authors.initials: S
authors.lastname: Kupchinsky
authors.forename: Michael
authors.initials: M
authors.lastname: Siu
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Taylor
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Theodore O
authors.initials: TO
authors.lastname: Johnson
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Dress
authors.forename: Martin P
authors.initials: MP
authors.lastname: Edwards
authors.forename: Sue
authors.initials: S
authors.lastname: Zhou
authors.forename: Natilie A
authors.initials: NA
authors.lastname: Hosea
authors.forename: Amy
authors.initials: A
authors.lastname: Lapaglia
authors.forename: Ping
authors.initials: P
authors.lastname: Kang
authors.forename: Arturo
authors.initials: A
authors.lastname: Castro
authors.forename: Jacques
authors.initials: J
authors.lastname: Ermolieff
authors.forename: Andrea
authors.initials: A
authors.lastname: Fanjul
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Vogel
authors.forename: Paul
authors.initials: P
authors.lastname: Rejto
authors.forename: Deepak
authors.initials: D
authors.lastname: Dalvie
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000631:Aminopyridines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D005978:Glutathione / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006801:Humans; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: C525872:4'-cyanobiphenyl-4-sulfonic acid (6-aminopyridin-2-yl)amide; D000631:Aminopyridines; D013449:Sulfonamides; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005978:Glutathione