title: The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus.
abstract: A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation.
authors.affiliation: Pfizer Wordwide Research and Development, Eastern Point Road, Groton, CT 06442, USA. aguzmanp@amgen.com
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.forename: Esther C Y
authors.initials: EC
authors.lastname: Lee
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Stevens
authors.forename: Gary E
authors.initials: GE
authors.lastname: Aspnes
authors.forename: Jianwei
authors.initials: J
authors.lastname: Bian
authors.forename: Mary T
authors.initials: MT
authors.lastname: Didiuk
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.forename: Dianna
authors.initials: D
authors.lastname: Moore
authors.forename: Christian
authors.initials: C
authors.lastname: Perreault
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Sammons
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.forename: Janice
authors.initials: J
authors.lastname: Brown
authors.forename: Karen
authors.initials: K
authors.lastname: Atkinson
authors.forename: John
authors.initials: J
authors.lastname: Litchfield
authors.forename: Beijing
authors.initials: B
authors.lastname: Tan
authors.forename: Brian
authors.initials: B
authors.lastname: Samas
authors.forename: William J
authors.initials: WJ
authors.lastname: Zavadoski
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Salatto
authors.forename: Judith
authors.initials: J
authors.lastname: Treadway
mesh_terms: D000818:Animals; D002627:Chemistry, Physical; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004847:Epithelial Cells / Q000187:drug effects; D000882:Haplorhini; D006801:Humans; D008099:Liver / Q000166:cytology; D051379:Mice; D015394:Molecular Structure; D011422:Propionates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011422:Propionates; D018027:Receptors, Glucagon; D054852:Small Molecule Libraries