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

Lotte Bjerre Knudsen; Dan Kiel; Min Teng; Carsten Behrens; Dilip Bhumralkar; János T Kodra; Jens Juul 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

doi:10.1073/pnas.0605701104

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

Lotte Bjerre Knudsen, Dan Kiel, Min Teng, Carsten Behrens, Dilip Bhumralkar, János T Kodra, Jens Juul 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 TruesdaleJohn May, Jesper Lau

Endocrinology and Metabolism

167 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Proceedings of the National Academy of Sciences of the United States of America
Vol/bind	104
Udgave nummer	3
Sider (fra-til)	937-42
Antal sider	6
ISSN	0027-8424
DOI	https://doi.org/10.1073/pnas.0605701104
Status	Udgivet - 16 jan. 2007

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10.1073/pnas.0605701104

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Knudsen, L. B., Kiel, D., Teng, M., Behrens, C., Bhumralkar, D., Kodra, J. T., Holst, J. J., Jeppesen, C. B., Johnson, M. D., de Jong, J. C., Jorgensen, A. S., Kercher, T., Kostrowicki, J., Madsen, P., Olesen, P. H., Petersen, J. S., Poulsen, F., Sidelmann, U. G., Sturis, J., ... Lau, J. (2007). Small-molecule agonists for the glucagon-like peptide 1 receptor. Proceedings of the National Academy of Sciences of the United States of America, 104(3), 937-42. https://doi.org/10.1073/pnas.0605701104

Knudsen, LB, Kiel, D, Teng, M, Behrens, C, Bhumralkar, D, Kodra, JT, Holst, JJ, Jeppesen, CB, Johnson, MD, de Jong, JC, Jorgensen, AS, Kercher, T, Kostrowicki, J, Madsen, P, Olesen, PH, Petersen, JS, Poulsen, F, Sidelmann, UG, Sturis, J, Truesdale, L, May, J & Lau, J 2007, 'Small-molecule agonists for the glucagon-like peptide 1 receptor', Proceedings of the National Academy of Sciences of the United States of America, bind 104, nr. 3, s. 937-42. https://doi.org/10.1073/pnas.0605701104

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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.",

keywords = "Animals, Cells, Cultured, Cricetinae, Drug Evaluation, Preclinical, Glucagon-Like Peptides, Humans, Insulin, Mice, Mice, Knockout, Molecular Structure, Pancreas, Perfusion, Quinoxalines, Receptors, Glucagon, Sulfones, Thiadiazoles",

author = "Knudsen, {Lotte Bjerre} and Dan Kiel and Min Teng and Carsten Behrens and Dilip Bhumralkar and Kodra, {J{\'a}nos T} and Holst, {Jens Juul} and Jeppesen, {Claus B} and Johnson, {Michael D} and {de Jong}, {Johannes Cornelis} and Jorgensen, {Anker Steen} and Tim Kercher and Jarek Kostrowicki and Peter Madsen and Olesen, {Preben H} and Petersen, {Jacob S} and Fritz Poulsen and Sidelmann, {Ulla G} and Jeppe Sturis and Larry Truesdale and John May and Jesper Lau",

year = "2007",

month = jan,

day = "16",

doi = "10.1073/pnas.0605701104",

language = "English",

volume = "104",

pages = "937--42",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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T1 - Small-molecule agonists for the glucagon-like peptide 1 receptor

AU - Knudsen, Lotte Bjerre

AU - Kiel, Dan

AU - Teng, Min

AU - Behrens, Carsten

AU - Bhumralkar, Dilip

AU - Kodra, János T

AU - Holst, Jens Juul

AU - Jeppesen, Claus B

AU - Johnson, Michael D

AU - de Jong, Johannes Cornelis

AU - Jorgensen, Anker Steen

AU - Kercher, Tim

AU - Kostrowicki, Jarek

AU - Madsen, Peter

AU - Olesen, Preben H

AU - Petersen, Jacob S

AU - Poulsen, Fritz

AU - Sidelmann, Ulla G

AU - Sturis, Jeppe

AU - Truesdale, Larry

AU - May, John

AU - Lau, Jesper

PY - 2007/1/16

Y1 - 2007/1/16

N2 - 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.

AB - 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.

KW - Animals

KW - Cells, Cultured

KW - Cricetinae

KW - Drug Evaluation, Preclinical

KW - Glucagon-Like Peptides

KW - Humans

KW - Insulin

KW - Mice

KW - Mice, Knockout

KW - Molecular Structure

KW - Pancreas

KW - Perfusion

KW - Quinoxalines

KW - Receptors, Glucagon

KW - Sulfones

KW - Thiadiazoles

U2 - 10.1073/pnas.0605701104

DO - 10.1073/pnas.0605701104

M3 - Journal article

C2 - 17213325

SN - 0027-8424

VL - 104

SP - 937

EP - 942

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 3

ER -

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

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