Piperazine sulfonamides as potent, selective, and orally available 11beta-hydroxysteroid dehydrogenase type 1 inhibitors with efficacy in the rat cortisone-induced hyperinsulinemia model.
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.
Xiang
Jason
J
Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA. jxiang@wyeth.com
Wan
Zhao-Kui
ZK
Li
Huan-Qiu
HQ
Ipek
Manus
M
Binnun
Eva
E
Nunez
Jill
J
Chen
Lihren
L
McKew
John C
JC
Mansour
Tarek S
TS
Xu
Xin
X
Suri
Vipin
V
Tam
May
M
Xing
Yuzhe
Y
Li
Xiangping
X
Hahm
Seung
S
Tobin
James
J
Saiah
Eddine
E
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
D004791:Enzyme Inhibitors; D010879:Piperazines; D013449:Sulfonamides; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003348:Cortisone