title: Design and synthesis of conformationally constrained tri-substituted ureas as potent antagonists of the human glucagon receptor.
abstract: A series of conformationally constrained tri-substituted ureas were synthesized, and their potential as glucagon receptor antagonists was evaluated. This effort resulted in the identification of compound 4a, which had a binding IC50 of 4.0 nM and was shown to reduce blood glucose levels at 3 mg/kg in glucagon-challenged mice containing a humanized glucagon receptor. Compound 4a was efficacious in correcting hyperglycemia induced by a high fat diet in transgenic mice at an oral dose as low as 3 mg/kg.
authors.affiliation: Department of Basic Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. rui_liang@merck.com
authors.forename: Rui
authors.initials: R
authors.lastname: Liang
authors.forename: Lauren
authors.initials: L
authors.lastname: Abrardo
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Brady
authors.forename: Mari Rios
authors.initials: MR
authors.lastname: Candelore
authors.forename: Victor
authors.initials: V
authors.lastname: Ding
authors.forename: Richard
authors.initials: R
authors.lastname: Saperstein
authors.forename: Laurie M
authors.initials: LM
authors.lastname: Tota
authors.forename: Michael
authors.initials: M
authors.lastname: Wright
authors.forename: Steve
authors.initials: S
authors.lastname: Mock
authors.forename: Constantin
authors.initials: C
authors.lastname: Tamvakopolous
authors.forename: Sharon
authors.initials: S
authors.lastname: Tong
authors.forename: Song
authors.initials: S
authors.lastname: Zheng
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: Emma R
authors.initials: ER
authors.lastname: Parmee
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004041:Dietary Fats; D015195:Drug Design; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D005934:Glucagon / Q000037:antagonists & inhibitors; D006207:Half-Life; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000517:prevention & control; D007202:Indicators and Reagents; D051379:Mice; D008822:Mice, Transgenic; D008968:Molecular Conformation; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000235:genetics; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007202:Indicators and Reagents; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D014508:Urea; D005934:Glucagon; D000242:Cyclic AMP