Piperazine sulfonamides as potent, selective, and orally available 11beta-hydroxysteroid dehydrogenase type 1 inhibitors with efficacy in the rat cortisone-induced hyperinsulinemia model

• Published in: Journal of medicinal chemistry Vol. 51; no. 14; p. 4068
• Main Authors: Xiang, Jason, Wan, Zhao-Kui, Li, Huan-Qiu, Ipek, Manus, Binnun, Eva, Nunez, Jill, Chen, Lihren, McKew, John C, Mansour, Tarek S, Xu, Xin, Suri, Vipin, Tam, May, Xing, Yuzhe, Li, Xiangping, Hahm, Seung, Tobin, James, Saiah, Eddine
• Format: Journal Article
• Language: English
• Published: United States 24.07.2008
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; Administration, Oral; Animals; Biological Availability; Cortisone - pharmacology; Disease Models, Animal; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Hyperinsulinism - chemically induced; Hyperinsulinism - drug therapy; Hyperinsulinism - enzymology; Piperazines - administration & dosage; Piperazines - pharmacokinetics; Piperazines - pharmacology; Piperazines - therapeutic use; Rats; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; Sulfonamides - therapeutic use
• ISSN: 1520-4804
• DOI: 10.1021/jm8004948

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.