Eleven Amino Acid Glucagon-like Peptide-1 Receptor Agonists with Antidiabetic Activity

作者：Claudio Mapelli, Sesha Natarajan, Jean‐Philippe Meyer, Margarita Bastos, Michael S. Bernatowicz, Ving G. Lee, Jelka Pluščec, Douglas J. Riexinger, Ellen S. Sieber-McMaster, Keith L. Constantine, Constance A. Smith-Monroy, Rajasree Golla, Zhengping Ma, Daniel Angelo Longhi, Dan Shi, Xin Li, Joseph R. Taylor, Barry Koplowitz, Cecilia L. Chi, Ashish Khanna, Gordon W. Robinson, Ramakrishna Seethala, Ildiko Antal‐Zimanyi, Robert H. Stoffel, Song‐Ping Han, Jean M. Whaley, Christine Huang, John Krupinski, William R. Ewing · 发表于：Journal of Medicinal Chemistry · 年份：2009 · DOI：10.1021/jm900752a · 被引用次数：74 · 研究领域：Diabetes Treatment and Management、Neuropeptides and Animal Physiology、Receptor Mechanisms and Signaling

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.