N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275.
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.
Siu
Michael
M
Discovery Chemistry, Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States. siu.michael@gene.com
Johnson
Theodore O
TO
Wang
Yong
Y
Nair
Sajiv K
SK
Taylor
Wendy D
WD
Cripps
Stephan J
SJ
Matthews
Jean J
JJ
Edwards
Martin P
MP
Pauly
Thomas A
TA
Ermolieff
Jacques
J
Castro
Arturo
A
Hosea
Natilie A
NA
LaPaglia
Amy
A
Fanjul
Andrea N
AN
Vogel
Jennifer E
JE
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
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