Identification and synthesis of potent and selective pyridyl-isoxazole based agonists of sphingosine-1-phosphate 1 (S1P₁)

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• 作者：Junqing Guo ; ^{junqing.guo@bms.com" class="auth_mail" title="E-mail the corresponding author} ; Scott H. Watterson ; Steven H. Spergel ; James Kempson ; Charles M. Langevine ; 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&rsquo ; Arienzo ; Anthony Marino ; Praveen Balimane ; Luisa Salter-Cid ; Murray McKinnon ; Joel C. Barrish ; Percy H. Carter ; William J. Pitts ; Jenny Xie ; Alaric J. Dyckman
• 关键词：Sphingosine-1-phosphate ; Sphingosine-1-phosphate 1 ; S1P1 ; Isoxazole ; FTY720 ; Fingolimod
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：26
• 期：10
• 页码：2470-2474
• 全文大小：868 K

文摘

The synthesis and structure–activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P₁ are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.