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A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America . 1/16/2007, Vol. 104 Issue 3, p943-948. 6p. 4 Graphs. - Publication Year :
- 2007
-
Abstract
- Peptidic mimics of the gut hormone glucagon-like peptide (GLP) 1, exemplified by the recently approved drug exenatide, show promise as therapies for type 2 diabetes. Such "incretin mimetics" regulate glucose appearance in the plasma and can restore glucose-stimulated insulin secretion without excess risk of hypoglycemia. The need for injection, which may limit the use of peptidic GLP-1 receptor (GLP-1R) agonists, has driven largely unsuccessful efforts to find smaller molecules. The failure to identify orally effective agonists has instead promoted the indirect approach of inhibiting the GLP-1-degrading enzyme dipeptidyl peptidase IV. Here we report a nonpeptidic GLP-1R agonist with sufficient activity to evoke effects in whole animals, including antidiabetic efficacy in db/db mice. Two substituted cyclobutanes (S4P and Boc5) were developed after screening a compound library against a cell line stably cotransfected with GIP-1R and a cAMP-responsive reporter. Each bound to GLP-1R and increased intracellular cAMP. Agonist effects were blocked by the GLP-1R antagonist exendin(9-39). Boc5 amplified glucose-stimulated insulin secretion in isolated rat islets. Both i.p. and oral administration of Boc5 dose-dependently inhibited food intake in mice, an effect that could be blocked by pretreatment with exendin(9-39). Daily injections of BocS into dbldb mice reduced HbA1c to nondiabetic values, an effect not observed in ad libitum-fed or pair-fed diabetic controls. Thus, Boc5 behaved as a full GLP-1 mimetic in vitro and in vivo. The chemical genus represented by BocS may prompt the exploration of orally available GLP-1R agonists with potential utility in diabetes and obesity. [ABSTRACT FROM AUTHOR]
- Subjects :
- *GLUCAGON-like peptide 1
*PEPTIDE hormones
*PEPTIDES
*DIABETES
*GLUCOSE
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 104
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 23880832
- Full Text :
- https://doi.org/10.1073/pnas.0610173104