Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor

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• 作者：Daniel J. Buzard ; Sun Hee Kim ; Luis Lopez ; Andrew Kawasaki ; Xiuwen Zhu ; Jeanne Moody ; Lars Thoresen ; Imelda Calderon ; Brett Ullman ; Sangdon Han ; Juerg Lehmann ; Tawfik Gharbaoui ; Dipanjan Sengupta ; Lorene Calvano ; Antonio Garrido Montalban ; You-An Ma ; Carleton Sage ; Yinghong Gao ; Graeme Semple ; Jeff Edwards ; Jeremy Barden ; Michael Morgan ; Weichao Chen ; Khawja Usmani ; Chuan Chen ; Abu Sadeque ; Ronald J. Christopher ; Jayant Thatte ; Lixia Fu ; Michelle Solomon ; David Mills ; Kevin Whelan ; Hussien Al-Shamma ; Joel Gatlin ; Minh Le ; Ibragim Gaidarov ; Todd Anthony ; David J. Unett ; Anthony Blackburn ; Jaimie Rueter ; Scott Stirn ; 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：1313-1317
• 全文大小：261K
• ISSN：1948-5875

文摘

APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P₁ receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P₁ and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.

Keywords:

Sphingosine-1-phosphate; S1P₁; APD334; gilenya; FTY720; fingolimod