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

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...