2. Academic Validation
  3. 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

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

Affiliation

  • 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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