Discovery and Structure–Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P1)

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• 作者：John L. Gilmore ; James E. Sheppeck II ; Scott H. Watterson ; Lauren Haque ; Parag Mukhopadhyay ; Andrew J. Tebben ; Michael A. Galella ; Ding Ren Shen ; Melissa Yarde ; Mary Ellen Cvijic ; Virna Borowski ; Kathleen Gillooly ; Tracy Taylor ; Kim W. McIntyre ; Bethanne Warrack ; Paul C. Levesque ; Julia P. Li ; Georgia Cornelius ; Celia D’Arienzo ; Anthony Marino ; Praveen Balimane ; Luisa Salter-Cid ; Joel C. Barrish ; William J. Pitts ; Percy H. Carter ; Jenny Xie ; Alaric J. Dyckman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6248-6264
• 全文大小：741K
• 年卷期：0
• ISSN：1520-4804

文摘

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P₁ receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P₁ agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P₁ agonists such as compounds 18a and 19a which have greater than 1000-fold selectivity over S1P₃ are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound 19a was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE).