(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acids as S1P1 Functional Antagonists

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• 作者：Daniel J. Buzard ; Luis Lopez ; Jeanne Moody ; Andrew Kawasaki ; Thomas O. Schrader ; Michelle Kasem ; Ben Johnson ; Xiuwen Zhu ; Lars Thoresen ; Sun Hee Kim ; Tawfik Gharbaoui ; Dipanjan Sengupta ; Lorene Calvano ; Ashwin Krishnan ; Yinghong Gao ; Graeme Semple ; Jeff Edwards ; Jeremy Barden ; Michael Morgan ; Khawja Usmani ; Chuan Chen ; Abu Sadeque ; Weichao Chen ; Ronald J. Christopher ; Jayant Thatte ; Lixia Fu ; Michelle Solomon ; Kevin Whelan ; Hussien Al-Shamma ; Joel Gatlin ; Ibragim Gaidarov ; Todd Anthony ; Minh Le ; David J. Unett ; Scott Stirn ; Anthony Blackburn ; Dominic P. Behan ; Robert M. Jones
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：5
• 期：12
• 页码：1334-1339
• 全文大小：262K
• ISSN：1948-5875

文摘

S1P₁ is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P₁ functional antagonists, with favorable pharmacokinetic and safety properties.

Keywords:

Sphingosine-1-phosphate; S1P1 agonist; FTY720; fingolimod; Gilenya