Novel S1P1 receptor agonists - Part 3: From thiophenes to pyridines

Article abstract of DOI:10.1021/jm4014696

In preceding communications we summarized our medicinal chemistry efforts leading to the identification of potent, selective, and orally active S1P ₁ 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 S1P ₁ 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.