title: N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275.
abstract: N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.
authors.affiliation: Discovery Chemistry, Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States. siu.michael@gene.com
authors.forename: Michael
authors.initials: M
authors.lastname: Siu
authors.forename: Theodore O
authors.initials: TO
authors.lastname: Johnson
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Sajiv K
authors.initials: SK
authors.lastname: Nair
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Taylor
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Cripps
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Matthews
authors.forename: Martin P
authors.initials: MP
authors.lastname: Edwards
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Pauly
authors.forename: Jacques
authors.initials: J
authors.lastname: Ermolieff
authors.forename: Arturo
authors.initials: A
authors.lastname: Castro
authors.forename: Natilie A
authors.initials: NA
authors.lastname: Hosea
authors.forename: Amy
authors.initials: A
authors.lastname: LaPaglia
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Fanjul
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Vogel
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D006224:Cricetinae; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: C525872:4'-cyanobiphenyl-4-sulfonic acid (6-aminopyridin-2-yl)amide; D000631:Aminopyridines; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1