title: Piperazine sulfonamides as potent, selective, and orally available 11beta-hydroxysteroid dehydrogenase type 1 inhibitors with efficacy in the rat cortisone-induced hyperinsulinemia model.
abstract: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. Evidence suggests that selective inhibition of 11beta-HSD1 could treat diabetes and metabolic syndrome. Presented herein are the synthesis, structure-activity relationship, and in vivo evaluation of piperazine sulfonamides as 11beta-HSD1 inhibitors. Through modification of our initial lead 5a, we have identified potent and selective 11beta-HSD1 inhibitors such as 13q and 13u with good pharmacokinetic properties.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA. jxiang@wyeth.com
authors.forename: Jason
authors.initials: J
authors.lastname: Xiang
authors.forename: Zhao-Kui
authors.initials: ZK
authors.lastname: Wan
authors.forename: Huan-Qiu
authors.initials: HQ
authors.lastname: Li
authors.forename: Manus
authors.initials: M
authors.lastname: Ipek
authors.forename: Eva
authors.initials: E
authors.lastname: Binnun
authors.forename: Jill
authors.initials: J
authors.lastname: Nunez
authors.forename: Lihren
authors.initials: L
authors.lastname: Chen
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Vipin
authors.initials: V
authors.lastname: Suri
authors.forename: May
authors.initials: M
authors.lastname: Tam
authors.forename: Yuzhe
authors.initials: Y
authors.lastname: Xing
authors.forename: Xiangping
authors.initials: X
authors.lastname: Li
authors.forename: Seung
authors.initials: S
authors.lastname: Hahm
authors.forename: James
authors.initials: J
authors.lastname: Tobin
authors.forename: Eddine
authors.initials: E
authors.lastname: Saiah
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003348:Cortisone / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006946:Hyperinsulinism / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D010879:Piperazines; D013449:Sulfonamides; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003348:Cortisone