Novel S1P1 receptor agonists – Part 5: From amino-to alkoxy-pyridines

• DOI: 10.1016/j.ejmech.2016.03.020
• Publication Date: 2016-03-12T07:57:46Z
• Authors: Martin H. Bolli; Cyrille Lescop; Magdalena Birker; Ruben de Kanter; Patrick Hess; Christopher Kohl; Oliver Nayler; Markus Rey; Patrick Sieber; Jörg Velker; Thomas Weller; Beat Steiner
• Keywords: Male; 0301 basic medicine; Receptors, Lysosphingolipid; Structure-Activity Relationship; 0303 health sciences; 03 medical and health sciences; Pyridines; Proton Magnetic Resonance Spectroscopy; Animals; Rats, Wistar; Rats; 3. Good health

In a previous communication we reported on the discovery of aminopyridine 1 as a potent, selective and orally active S1P1 receptor agonist. More detailed studies revealed that this compound is phototoxic in vitro. As a result of efforts aiming at eliminating this undesired property, a series of alkoxy substituted pyridine derivatives was discovered. The photo irritancy factor (PIF) of these alkoxy pyridines was significantly lower than the one of aminopyridine 1 and most compounds were not phototoxic. Focused SAR studies showed, that 2-, 3-, and 4-pyridine derivatives delivered highly potent S1P1 receptor agonists. While the 2-pyridines were clearly more selective against S1PR3, the corresponding 3- or 4-pyridine analogues showed significantly longer oral half-lives and as a consequence longer pharmacological duration of action after oral administration. One of the best compounds, cyclopentoxy-pyridine 45b lacked phototoxicity, showed EC50 values of 0.7 and 140 nM on S1PR1 and S1PR3, respectively, and maximally reduced the blood lymphocyte count for at least 24 h after oral administration of 10 mg/kg to Wistar rats.