| Literature DB >> 19702274 |
Claudio Mapelli1, Sesha I Natarajan, Jean-Philippe Meyer, Margarita M Bastos, Michael S Bernatowicz, Ving G Lee, Jelka Pluscec, Douglas J Riexinger, Ellen S Sieber-McMaster, Keith L Constantine, Constance A Smith-Monroy, Rajasree Golla, Zhengping Ma, Daniel A Longhi, Dan Shi, Li Xin, Joseph R Taylor, Barry Koplowitz, Cecilia L Chi, Ashish Khanna, Gordon W Robinson, Ramakrishna Seethala, Ildiko A Antal-Zimanyi, Robert H Stoffel, Songping Han, Jean M Whaley, Christine S Huang, John Krupinski, William R Ewing.
Abstract
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.Entities:
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Year: 2009 PMID： 19702274 DOI： 10.1021/jm900752a
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446