Novel S1P(1) receptor agonists--part 3: from thiophenes to pyridines

J Med Chem. 2014 Jan 9;57(1):110-30. doi: 10.1021/jm4014696.

Martin H Bolli ¹, 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, Jörg Velker, Thomas Weller

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Affiliation

1 Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.

PMID: 24367923 DOI: 10.1021/jm4014696

Abstract

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' 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.

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