title: Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insulinotropic polypeptide receptor.
abstract: Optimization of a new series of small molecule human glucagon receptor (hGluR) antagonists is described. In the process of optimizing glucagon receptor antagonists, we counter-screened against the closely related human gastric inhibitory polypeptide receptor (hGIPR), and through structure activity analysis, we obtained compounds with low nanomolar affinities toward the hGluR, which were selective against the hGIPR and the human glucagon-like peptide-1 receptor (hGLP-1R). In the best cases, we obtained a >50 fold selectivity for the hGluR over the hGIPR and a >1000 fold selectivity over the hGLP-1R. A potent and selective glucagon receptor antagonist was demonstrated to inhibit glucagon-induced glycogenolysis in primary rat hepatocytes as well as to lower glucagon-induced hyperglycemia in Sprague-Dawley rats. Furthermore, the compound was shown to lower blood glucose in the ob/ob mouse after oral dosing.
authors.affiliation: Department of Diabetes Protein Engineering, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. jtk@novonordisk.com
authors.forename: János T
authors.initials: JT
authors.lastname: Kodra
authors.forename: Anker Steen
authors.initials: AS
authors.lastname: Jørgensen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Andersen
authors.forename: Carsten
authors.initials: C
authors.lastname: Behrens
authors.forename: Christian Lehn
authors.initials: CL
authors.lastname: Brand
authors.forename: Inger Thøger
authors.initials: IT
authors.lastname: Christensen
authors.forename: Mette
authors.initials: M
authors.lastname: Guldbrandt
authors.forename: Claus Bekker
authors.initials: CB
authors.lastname: Jeppesen
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Knudsen
authors.forename: Peter
authors.initials: P
authors.lastname: Madsen
authors.forename: Erica
authors.initials: E
authors.lastname: Nishimura
authors.forename: Christian
authors.initials: C
authors.lastname: Sams
authors.forename: Ulla G
authors.initials: UG
authors.lastname: Sidelmann
authors.forename: Raymon A
authors.initials: RA
authors.lastname: Pedersen
authors.forename: Francis C
authors.initials: FC
authors.lastname: Lynn
authors.forename: Jesper
authors.initials: J
authors.lastname: Lau
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002478:Cells, Cultured; D050261:Glycogenolysis / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*; D051379:Mice; D008820:Mice, Obese; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; C041086:gastric inhibitory polypeptide receptor