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-dimethylpent

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• 作者：Duane DeMong ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2601-2610
• 全文大小：529K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

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.