Development of Novel Benzomorpholine Class of Diacylglycerol Acyltransferase I Inhibitors

Diacylglycerol acyltransferase 1 (DGAT1) presents itself as a potential therapeutic target for obesity and diabetes for its important role in triglyceride biosynthesis. Herein we report the rational design of a novel class of DGAT1 inhibitors featuring a benzomorpholine core (<b>23n</b>). SAR exploration yielded compounds with good potency and selectivity as well as reasonable physical and pharmacokinetic properties. This class of DGAT1 inhibitors was tested in rodent models to evaluate DGAT1 inhibition as a novel approach for the treatment of metabolic diseases. Compound <b>23n</b> conferred weight loss and a reduction in liver triglycerides when dosed chronically in mice with diet-induced obesity and depleted serum triglycerides following a lipid challenge

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