ABSTRACT
A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-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 1 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 1, 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.
Subject(s)
Benzamides/chemical synthesis , Benzamides/pharmacology , Receptors, Glucagon/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Animals , Blood Glucose/metabolism , Cyclohexanones/chemistry , Cyclohexanones/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Diet, High-Fat , Drug Discovery , Glucagon/pharmacology , Mice , Mice, Inbred ICR , Obesity/drug therapy , Prediabetic State/drug therapy , Prediabetic State/metabolism , Structure-Activity RelationshipABSTRACT
The asymmetric total synthesis of (+)-crassalactone D (4), a naturally occurring antitumor agent, has been achieved by employing an oxidative spirocyclization of furan 11 as the key step. Two close analogues, 7-epi-crassalactone D (14) and 5-epi-7-epi-crassalactone D (15), also have been prepared in the course of the synthesis of (+)-crassalactone D.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Furans/chemical synthesis , Spiro Compounds/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Cyclization , Furans/chemistry , Spiro Compounds/chemistry , StereoisomerismABSTRACT
Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit arteriovenous-shunt (AV) thrombosis model.
