The discovery of 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 and selective glucagon receptor antagonist.

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.

DOI: 10.1021/jm401858f

Cite this paper

@article{Demong2014TheDO, title={The discovery of 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 and selective glucagon receptor antagonist.}, author={Duane Demong and X. G. Dai and Joyce J. Hwa and Michael W. Miller and Sue-Ing Lin and Ling Kang and Andrew W. Stamford and William J. Greenlee and Wensheng Yu and Michael K. Wong and Brian J Lavey and Joseph A Kozlowski and Guowei Zhou and De-yi Yang and Bhuneshwari Patel and Aileen Soriano and Ying Zhai and Christopher Sondey and Hongtao Zhang and Jean E Lachowicz and Diane E. Grotz and Kathleen A Cox and Richard A. Morrison and Teresa Andreani and Yang Cao and Mark Liang and Tao Meng and Paul McNamara and Jesse C S Wong and Prudence Bradley and Kung-I Feng and Jitendra D. Belani and Ping Chen and Peng Dai and Jolicia F Gauuan and Peishan Lin and He Zhao}, journal={Journal of medicinal chemistry}, year={2014}, volume={57 6}, pages={2601-10} }