Discovery of a Potent Thiadiazole Class of Histamine H-3 Receptor Antagonist for the Treatment of Diabetes

[摘要]：A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H-3 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 HbA(1c) after 12 days of treatment.

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