2 research outputs found
Discovery of a Potent Thiadiazole Class of Histamine H<sub>3</sub> Receptor Antagonist for the Treatment of Diabetes
A series of novel 2-piperidinopiperidine thiadiazoles
were synthesized
and evaluated as new leads of histamine H<sub>3</sub> receptor antagonists.
The 4-(5-([1,4′-bipiperidin]-1′-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)Âmorpholine
(<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<sub>1c</sub> 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 EC<sub>50</sub> 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