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ACS Med Chem Lett. 2011 Nov 21;3(3):198-202. doi: 10.1021/ml200250t. eCollection 2012 Mar 8.

Discovery of a potent thiadiazole class of histamine h3 receptor antagonist for the treatment of diabetes.

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Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.


A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H3 receptor antagonists. The 4-(5-([1,4'-bipiperidin]-1'-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 HbA1c after 12 days of treatment.


H3; HbA1c; Histamine; antagonist; non-fasting glucose; thiadiazole; type 2 diabetes

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