2. Academic Validation
  3. Small-molecule agonists for the glucagon-like peptide 1 receptor

Small-molecule agonists for the glucagon-like peptide 1 receptor

  • Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):937-42. doi: 10.1073/pnas.0605701104.
Lotte Bjerre Knudsen 1,  Dan Kiel,  Min Teng,  Carsten Behrens,  Dilip Bhumralkar,  János T Kodra,  Jens J Holst,  Claus B Jeppesen,  Michael D Johnson,  Johannes Cornelis de Jong,  Anker Steen Jorgensen,  Tim Kercher,  Jarek Kostrowicki,  Peter Madsen,  Preben H Olesen,  Jacob S Petersen,  Fritz Poulsen,  Ulla G Sidelmann,  Jeppe Sturis,  Larry Truesdale,  John May,  Jesper Lau
Affiliations

Affiliation

  • 1 Department of Discovery Biology, Novo Nordisk Als, Novo Nordisk Park, DK-2760 Maaloev, Denmark. lbkn@novonordisk.com
PMID: 17213325 DOI: 10.1073/pnas.0605701104
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.

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