Eleven Amino Acid Glucagon-like Peptide-1 Receptor Agonists with Antidiabetic Activity
| Autor: | Claudio Mapelli, Ramakrishna Seethala, Songping Han, Ellen Sieber-McMaster, William R. Ewing, Ashish Khanna, Keith L. Constantine, Douglas James Riexinger, Daniel Longhi, John Krupinski, Zhengping Ma, Constance Smith-Monroy, Bastos Margarita M, Dan Shi, Michael S. Bernatowicz, Joseph R. Taylor, Christine Huang, Rajasree Golla, Gordon William Robinson, Jelka Pluscec, Jean M. Whaley, Sesha Natarajan, Jean-Philippe Meyer, Robert H. Stoffel, Li Xin, Ving G. Lee, Barry Koplowitz, Cecilia L Chi, Ildiko Antal-Zimanyi |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Models Molecular endocrine system Protein Conformation Molecular Sequence Data Peptide CHO Cells Glucagon-Like Peptide-1 Receptor Mice chemistry.chemical_compound Cricetulus Dogs Cricetinae Drug Discovery Receptors Glucagon Peptide synthesis Animals Humans Hypoglycemic Agents Glucose homeostasis Amino Acid Sequence Receptor Peptide sequence Glucagon-like peptide 1 receptor chemistry.chemical_classification Dipeptide Dose-Response Relationship Drug digestive oral and skin physiology Amino acid chemistry Biochemistry Molecular Medicine Oligopeptides |
| Zdroj: | Journal of Medicinal Chemistry. 52:7788-7799 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm900752a |
| Popis: | Glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid peptide hormone that contributes to the physiological regulation of glucose homeostasis and food intake. Herein, we report the discovery of a novel class of 11 amino acid GLP-1 receptor agonists. These peptides consist of a structurally optimized 9-mer, which is closely related to the N-terminal 9 amino acids of GLP-1, linked to a substituted C-terminal biphenylalanine (BIP) dipeptide. SAR studies resulted in 11-mer GLP-1R agonists with similar in vitro potency to the native 30-mer. Peptides 21 and 22 acutely reduced plasma glucose excursions and increased plasma insulin concentrations in a mouse model of diabetes. These peptides also showed sustained exposures over several hours in mouse and dog models. The described 11-mer GLP-1 receptor agonists represent a new tool in further understanding GLP-1 receptor pharmacology that may lead to novel antidiabetic agents. |
| Databáze: | OpenAIRE |
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