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 (<b>5u</b>) displayed excellent potency and ex vivo receptor occupancy. Compound <b>5u</b> 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, <b>5u</b> dose dependently blocked the increase of HbA_1c after 12 days of treatment

Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia

Structure-guided optimization of a series of C-5 alkyl substituents led to the discovery of a potent nicotinic acid receptor agonist SCH 900271 (<b>33</b>) with an EC₅₀ of 2 nM in the hu-GPR109a assay. Compound <b>33</b> demonstrated good oral bioavailability in all species. Compound <b>33</b> exhibited dose-dependent inhibition of plasma free fatty acid (FFA) with 50% FFA reduction at 1.0 mg/kg in fasted male beagle dogs. Compound <b>33</b> had no overt signs of flushing at doses up to 10 mg/kg with an improved therapeutic window to flushing as compared to nicotinic acid. Compound <b>33</b> was evaluated in human clinical trials