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

The Discovery of <i>N</i>‑((2<i>H</i>‑Tetrazol-5-yl)methyl)-4-((<i>R</i>)‑1-((5<i>r</i>,8<i>R</i>)‑8‑(<i>tert</i>-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822): A Potent and Selective Glucagon Receptor Antagonist

A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound <b>1</b>, <i>N</i>-((2<i>H</i>-tetrazol-5-yl)­methyl)-4-((<i>R</i>)-1-((5<i>r</i>,8<i>R</i>)-8-(<i>tert</i>-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro­[4.5]­dec-3-en-1-yl)-4,4-dimethylpentyl)­benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of <b>1</b> lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound <b>1</b>, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice