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.
William R. Ewing合作论文数1Michael Bernatowicz合作论文数1Robert H Stoffel合作论文数1Barry Koplowitz合作论文数1Joseph R Taylor合作论文数1Rajasree Golla合作论文数1Eric M. Gordon合作论文数1Dan Shi合作论文数1Li Xin合作论文数1Cecilia L. Chi合作论文数1Seethala Ramakrishna合作论文数1Sesha I. Natarajan合作论文数1Jean-Philippe Meyer合作论文数1Zhengping Ma合作论文数1
Claudio Mapelli合作论文数1Douglas J. Riexinger合作论文数1Jean M Whaley合作论文数1Ellen S. Sieber-Mcmaster合作论文数1
Keith Constantine合作论文数1Daniel A. Longhi合作论文数1Gordon W. Robinson合作论文数1SP Han合作论文数1Margarita M. Bastos合作论文数1Ving G. Lee合作论文数1Ashish Khanna合作论文数1Christine Huang合作论文数1Constance A. Smith-Monroy合作论文数1John Krupinski合作论文数1
