Discovery of a Potent Thiadiazole Class of Histamine H3 Receptor Antagonist for the Treatment of Diabetes

详细信息    查看全文

• 作者：Ashwin U. Rao ; Ning Shao ; Robert G. Aslanian ; Tin-Yau Chan ; Sylvia J. Degrado ; Li Wang ; Brian McKittrick ; Mary Senior ; Robert E. West ; Jr. ; Shirley M. Williams ; Ren-Long Wu ; Joyce Hwa ; Bhuneshwari Patel ; Shuqin Zheng ; Christopher Sondey ; Anandan Palani
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：3
• 期：3
• 页码：198-202
• 全文大小：290K
• 年卷期：v.3,no.3(March 8, 2012)
• ISSN：1948-5875

文摘

A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H₃ receptor antagonists. The 4-(5-([1,4鈥?bipiperidin]-1鈥?yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u was also evaluated in vivo for antidiabetic efficacy in STZ diet-induced obesity type 2 diabetic mice for 2 or 12 days. Non-fasting glucose levels were significantly reduced as compared with vehicle-treated mice. In addition, 5u dose dependently blocked the increase of HbA_1c after 12 days of treatment.

Keywords:

Histamine; H₃; antagonist; thiadiazole; type 2 diabetes; non-fasting glucose; HbA_1c