title: Small-molecule agonists for the glucagon-like peptide 1 receptor.
abstract: 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.
authors.affiliation: Department of Discovery Biology, Novo Nordisk Als, Novo Nordisk Park, DK-2760 Maaloev, Denmark. lbkn@novonordisk.com
authors.forename: Lotte Bjerre
authors.initials: LB
authors.lastname: Knudsen
authors.forename: Dan
authors.initials: D
authors.lastname: Kiel
authors.forename: Min
authors.initials: M
authors.lastname: Teng
authors.forename: Carsten
authors.initials: C
authors.lastname: Behrens
authors.forename: Dilip
authors.initials: D
authors.lastname: Bhumralkar
authors.forename: János T
authors.initials: JT
authors.lastname: Kodra
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Claus B
authors.initials: CB
authors.lastname: Jeppesen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Johannes Cornelis
authors.initials: JC
authors.lastname: de Jong
authors.forename: Anker Steen
authors.initials: AS
authors.lastname: Jorgensen
authors.forename: Tim
authors.initials: T
authors.lastname: Kercher
authors.forename: Jarek
authors.initials: J
authors.lastname: Kostrowicki
authors.forename: Peter
authors.initials: P
authors.lastname: Madsen
authors.forename: Preben H
authors.initials: PH
authors.lastname: Olesen
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Petersen
authors.forename: Fritz
authors.initials: F
authors.lastname: Poulsen
authors.forename: Ulla G
authors.initials: UG
authors.lastname: Sidelmann
authors.forename: Jeppe
authors.initials: J
authors.lastname: Sturis
authors.forename: Larry
authors.initials: L
authors.lastname: Truesdale
authors.forename: John
authors.initials: J
authors.lastname: May
authors.forename: Jesper
authors.initials: J
authors.lastname: Lau
mesh_terms: 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*
chemical_list: 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