title: Identification of alkylidene hydrazides as glucagon receptor antagonists.
abstract: High throughput screening of our small molecule combinatorial library identified a class of benzoylnaphthalenehydrazones with modest affinity for the human glucagon receptor. Optimization of this initial hit through a series of targeted libraries and traditional medicinal chemistry led to ligands with nanomolar affinities. Pharmacological evaluation demonstrated that these ligands were competitive glucagon receptor antagonists. Intravenous administration of a representative benzoylnaphthalenehydrazone into rats attenuated glucagon-stimulated glucose levels.
authors.affiliation: Department of Medicinal Chemistry, Pfizer Global Research and Development, La Jolla/Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA. anthony.ling@agouron.com
authors.forename: A
authors.initials: A
authors.lastname: Ling
authors.forename: Y
authors.initials: Y
authors.lastname: Hong
authors.forename: J
authors.initials: J
authors.lastname: Gonzalez
authors.forename: V
authors.initials: V
authors.lastname: Gregor
authors.forename: A
authors.initials: A
authors.lastname: Polinsky
authors.forename: A
authors.initials: A
authors.lastname: Kuki
authors.forename: S
authors.initials: S
authors.lastname: Shi
authors.forename: K
authors.initials: K
authors.lastname: Teston
authors.forename: D
authors.initials: D
authors.lastname: Murphy
authors.forename: J
authors.initials: J
authors.lastname: Porter
authors.forename: D
authors.initials: D
authors.lastname: Kiel
authors.forename: J
authors.initials: J
authors.lastname: Lakis
authors.forename: K
authors.initials: K
authors.lastname: Anderes
authors.forename: J
authors.initials: J
authors.lastname: May
authors.forename: L B
authors.initials: LB
authors.lastname: Knudsen
authors.forename: J
authors.initials: J
authors.lastname: Lau
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D000242:Cyclic AMP / Q000096:biosynthesis; D005934:Glucagon / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C435934:3-chloro-4-hydroxy-N'-((4-hydroxy-1-naphthyl)methylidene)benzohydrazide; D001549:Benzamides; D001786:Blood Glucose; D006835:Hydrazones; D018027:Receptors, Glucagon; D005934:Glucagon; D000242:Cyclic AMP