Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insulinotropic polypeptide receptor.
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.
Kodra
János T
JT
Department of Diabetes Protein Engineering, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. jtk@novonordisk.com
Jørgensen
Anker Steen
AS
Andersen
Birgitte
B
Behrens
Carsten
C
Brand
Christian Lehn
CL
Christensen
Inger Thøger
IT
Guldbrandt
Mette
M
Jeppesen
Claus Bekker
CB
Knudsen
Lotte B
LB
Madsen
Peter
P
Nishimura
Erica
E
Sams
Christian
C
Sidelmann
Ulla G
UG
Pedersen
Raymon A
RA
Lynn
Francis C
FC
Lau
Jesper
J
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
D001786:Blood Glucose; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; C041086:gastric inhibitory polypeptide receptor