Small-molecule agonists for the glucagon-like peptide 1 receptor.
The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists.
Knudsen
Lotte Bjerre
LB
Department of Discovery Biology, Novo Nordisk Als, Novo Nordisk Park, DK-2760 Maaloev, Denmark. lbkn@novonordisk.com
Kiel
Dan
D
Teng
Min
M
Behrens
Carsten
C
Bhumralkar
Dilip
D
Kodra
János T
JT
Holst
Jens J
JJ
Jeppesen
Claus B
CB
Johnson
Michael D
MD
de Jong
Johannes Cornelis
JC
Jorgensen
Anker Steen
AS
Kercher
Tim
T
Kostrowicki
Jarek
J
Madsen
Peter
P
Olesen
Preben H
PH
Petersen
Jacob S
JS
Poulsen
Fritz
F
Sidelmann
Ulla G
UG
Sturis
Jeppe
J
Truesdale
Larry
L
May
John
J
Lau
Jesper
J
D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000601:surgery; D010477:Perfusion; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*
C517396:2-(2'-methyl)thiadiazolylsulfanyl-3-trifluoromethyl-6,7-dichloroquinoxaline; C517397:3-(tert-butylamino)-6,7-dichloro-2-(methylsulfonyl)quinoxaline; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D011810:Quinoxalines; D018027:Receptors, Glucagon; D013450:Sulfones; D013830:Thiadiazoles; D004763:Glucagon-Like Peptides