Fused tricyclic indoles as S1P₁ agonists with robust efficacy in animal models of autoimmune disease

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• 作者：Daniel J. Buzard ; ^{dbuzard@arenapharm.com} ; Sangdon Han ; Luis Lopez ; Andrew Kawasaki^&dagger ; ; Jeanne Moody^&Dagger ; ; Lars Thoresen ; Brett Ullman ; Juerg Lehmann ; Imelda Calderon ; Xiuwen Zhu ; Tawfik Gharbaoui^§ ; ; Dipanjan Sengupta^§ ; ; Ashwin Krishnan ; Yinghong Gao^¶ ; ; Jeff Edwards^鈥?/sup> ; Jeremy Barden ; Michael Morgan ; Khawja Usmani ; Chuan Chen ; Abu Sadeque ; Jayant Thatte^&dagger ; &dagger ; ; Michelle Solomon ; Lixia Fu^&Dagger ; &Dagger ; ; Kevin Whelan ; Ling Liu^§ ; § ; ; Hussien Al-Shamma ; Joel Gatlin ; Minh Le ; Charles Xing ; Sheryll Espinola^¶ ; ¶ ; ; Robert M. Jones
• 关键词：Sphingosine-1 phosphate receptor ; S1P1 agonist ; Immunomodulators ; FTY720
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 July, 2012
• 卷：22
• 期：13
• 页码：4404-4409
• 文件大小：615 K

摘要

Two series of fused tricyclic indoles were identified as potent and selective S1P₁ agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P₃ receptor in vitro, and correspondingly did not produce S1P₃ mediated bradycardia in telemeterized rat.