Potent and Selective Agonists of Sphingosine 1-Phosphate 1 (S1P1): Discovery and SAR of a Novel Isoxazole Based Series

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• 作者：Scott H. Watterson ; Junqing Guo ; Steve H. Spergel ; Charles M. Langevine ; Robert V. Moquin ; Ding Ren Shen ; Melissa Yarde ; Mary Ellen Cvijic ; Dana Banas ; Richard Liu ; Suzanne J. Suchard ; Kathleen Gillooly ; Tracy Taylor ; Sandra Rex-Rabe ; David J. Shuster ; Kim W. McIntyre ; Georgia Cornelius ; Celia D’Arienzo ; Anthony Marino ; Praveen Balimane ; Bethanne Warrack ; Luisa Salter-Cid ; Murray McKinnon ; Joel C. Barrish ; Percy H. Carter ; William J. Pitts ; Jenny Xie ; Alaric J. Dyckman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2820-2840
• 全文大小：666K
• ISSN：1520-4804

文摘

Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P<sub>1–5sub>) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P<sub>1sub>, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P<sub>1sub>. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.