AI Article Synopsis
- The research focused on developing effective S1P1 agonists, replacing the thiophene in a previously identified compound with pyridine derivatives, which resulted in less lipophilic and more selective agonists.
- The study assessed the structural features that affect receptor affinity and how well the compounds can move through the brain.
- Compound 53 emerged as a prime example, demonstrating strong efficacy in reducing blood lymphocyte counts in rats and favorable pharmacokinetic properties.
Article 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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