title: Human glucagon receptor antagonists based on alkylidene hydrazides.
abstract: A series of alkylidene hydrazide derivatives containing an alkoxyaryl moiety was optimized. The resulting hydrazide-ethers were competitive antagonists at the human glucagon receptor. Pharmacokinetic experiments showed fast clearance of most of the compounds tested. A representative compound [4-hydroxy-3-cyanobenzoic acid (4-isopropylbenzyloxy-3,5-dimethoxymethylene)hydrazide] with an IC50 value of 20 nM was shown to reduce blood glucose levels in fasted rats.
authors.affiliation: Pfizer Global Research and Development, 10770 Science Center Dr., San Diego, CA 92121, USA. anthony.ling@agouron.com
authors.forename: Anthony
authors.initials: A
authors.lastname: Ling
authors.forename: Michael
authors.initials: M
authors.lastname: Plewe
authors.forename: Javier
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Peter
authors.initials: P
authors.lastname: Madsen
authors.forename: Christian K
authors.initials: CK
authors.lastname: Sams
authors.forename: Jesper
authors.initials: J
authors.lastname: Lau
authors.forename: Vlad
authors.initials: V
authors.lastname: Gregor
authors.forename: Doug
authors.initials: D
authors.lastname: Murphy
authors.forename: Kimberly
authors.initials: K
authors.lastname: Teston
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kuki
authors.forename: Shenghua
authors.initials: S
authors.lastname: Shi
authors.forename: Larry
authors.initials: L
authors.lastname: Truesdale
authors.forename: Dan
authors.initials: D
authors.lastname: Kiel
authors.forename: John
authors.initials: J
authors.lastname: May
authors.forename: James
authors.initials: J
authors.lastname: Lakis
authors.forename: Kenna
authors.initials: K
authors.lastname: Anderes
authors.forename: Eugenia
authors.initials: E
authors.lastname: Iatsimirskaia
authors.forename: Ulla G
authors.initials: UG
authors.lastname: Sidelmann
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Knudsen
authors.forename: Christian L
authors.initials: CL
authors.lastname: Brand
authors.forename: Alex
authors.initials: A
authors.lastname: Polinsky
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001786:Blood Glucose / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D007267:Injections; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D006834:Hydrazines; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon