Novel S1P1 Receptor Agonists ? Part 3: From Thiophenes to Pyridines

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• 作者：Martin H. Bolli ; Stefan Abele ; Magdalena Birker ; Roberto Bravo ; Daniel Bur ; Ruben de Kanter ; Christopher Kohl ; Julien Grimont ; Patrick Hess ; Cyrille Lescop ; Boris Mathys ; Claus Müller ; Oliver Nayler ; Markus Rey ; Michael Scherz ; Gunther Schmidt ; Jürgen Seifert ; Beat Steiner ; J?rg Velker ; Thomas Weller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：January 9, 2014
• 年：2014
• 卷：57
• 期：1
• 页码：110-130
• 全文大小：667K
• ISSN：1520-4804

文摘

In preceding communications we summarized our medicinal chemistry efforts leading to the identification of potent, selective, and orally active S1P₁ agonists such as the thiophene derivative 1. As a continuation of these efforts, we replaced the thiophene in 1 by a 2-, 3-, or 4-pyridine and obtained less lipophilic, potent, and selective S1P₁ agonists (e.g., 2) efficiently reducing blood lymphocyte count in the rat. Structural features influencing the compounds鈥?receptor affinity profile and pharmacokinetics are discussed. In addition, the ability to penetrate brain tissue has been studied for several compounds. As a typical example for these pyridine based S1P₁ agonists, compound 53 showed EC₅₀ values of 0.6 and 352 nM for the S1P₁ and S1P₃ receptor, respectively, displayed favorable PK properties, and penetrated well into brain tissue. In the rat, compound 53 maximally reduced the blood lymphocyte count for at least 24 h after oral dosing of 3 mg/kg.