title: Discovery and structure-activity relationship of the first non-peptide competitive human glucagon receptor antagonists.
abstract: The first non-peptide competitive human glucagon receptor antagonist, 2-(benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethan one, NNC 92-1687 (2), is described. This antagonist has a binding affinity of 20 microM (IC50) and a functional Ki = 9.1 microM at the human glucagon receptor. A structure-activity relationship (SAR) was obtained on this compound, and the results show that only the benzimidazole part can be changed without complete loss of affinity. Analogues with tert-butyl or benzyloxy groups in the 5-position of the benzimidazole moiety were found to be equipotent or slightly more potent, all displaying binding affinities around 5-20 microM. Most of the changes to the catechol and the linker gave compounds without any affinity toward the human glucagon receptor. The 3-hydroxy group could, however, in the presence of a 4-hydroxy group be changed to a methoxy or a chloro group while retaining affinity.
authors.affiliation: Departments of Medicinal Chemistry, Molecular Pharmacology, Assay & Cell Technology, and Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Mâløv, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Madsen
authors.forename: L B
authors.initials: LB
authors.lastname: Knudsen
authors.forename: F C
authors.initials: FC
authors.lastname: Wiberg
authors.forename: R D
authors.initials: RD
authors.lastname: Carr
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C116536:2-(benzimidazo-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethanone; D001562:Benzimidazoles; D018027:Receptors, Glucagon