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

  • J Med Chem. 2014 Mar 27;57(6):2601-10. doi: 10.1021/jm401858f.
Duane DeMong  1 ,  Xing Dai ,  Joyce Hwa ,  Michael Miller ,  Sue-Ing Lin ,  Ling Kang ,  Andrew Stamford ,  William Greenlee ,  Wensheng Yu ,  Michael Wong ,  Brian Lavey ,  Joseph Kozlowski ,  Guowei Zhou ,  De-Yi Yang ,  Bhuneshwari Patel ,  Aileen Soriano ,  Ying Zhai ,  Christopher Sondey ,  Hongtao Zhang ,  Jean Lachowicz ,  Diane Grotz ,  Kathleen Cox ,  Richard Morrison ,  Teresa Andreani ,  Yang Cao ,  Mark Liang ,  Tao Meng ,  Paul McNamara ,  Jesse Wong ,  Prudence Bradley ,  Kung-I Feng ,  Jitendra Belani ,  Ping Chen ,  Peng Dai ,  Jolicia Gauuan ,  Peishan Lin ,  He Zhao
Affiliations
  • 1. Discovery and Preclinical Sciences, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
PMID: 24527772 DOI: 10.1021/jm401858f
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.

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