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.
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.
authors: Discovery and Preclinical Sciences, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Duane
authors: D
authors: DeMong
authors: Xing
authors: X
authors: Dai
authors: Joyce
authors: J
authors: Hwa
authors: Michael
authors: M
authors: Miller
authors: Sue-Ing
authors: SI
authors: Lin
authors: Ling
authors: L
authors: Kang
authors: Andrew
authors: A
authors: Stamford
authors: William
authors: W
authors: Greenlee
authors: Wensheng
authors: W
authors: Yu
authors: Michael
authors: M
authors: Wong
authors: Brian
authors: B
authors: Lavey
authors: Joseph
authors: J
authors: Kozlowski
authors: Guowei
authors: G
authors: Zhou
authors: De-Yi
authors: DY
authors: Yang
authors: Bhuneshwari
authors: B
authors: Patel
authors: Aileen
authors: A
authors: Soriano
authors: Ying
authors: Y
authors: Zhai
authors: Christopher
authors: C
authors: Sondey
authors: Hongtao
authors: H
authors: Zhang
authors: Jean
authors: J
authors: Lachowicz
authors: Diane
authors: D
authors: Grotz
authors: Kathleen
authors: K
authors: Cox
authors: Richard
authors: R
authors: Morrison
authors: Teresa
authors: T
authors: Andreani
authors: Yang
authors: Y
authors: Cao
authors: Mark
authors: M
authors: Liang
authors: Tao
authors: T
authors: Meng
authors: Paul
authors: P
authors: McNamara
authors: Jesse
authors: J
authors: Wong
authors: Prudence
authors: P
authors: Bradley
authors: Kung-I
authors: KI
authors: Feng
authors: Jitendra
authors: J
authors: Belani
authors: Ping
authors: P
authors: Chen
authors: Peng
authors: P
authors: Dai
authors: Jolicia
authors: J
authors: Gauuan
authors: Peishan
authors: P
authors: Lin
authors: He
authors: H
authors: Zhao
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D059305:Diet, High-Fat; D055808:Drug Discovery; D005934:Glucagon / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009765:Obesity / Q000188:drug therapy; D011236:Prediabetic State / Q000188:drug therapy / Q000378:metabolism; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D001786:Blood Glucose; D003512:Cyclohexanones; C000588585:N-((2H-tetrazol-5-yl)methyl)-4-(1-(8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro(4.5)dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide; D018027:Receptors, Glucagon; D013141:Spiro Compounds; D005934:Glucagon