1186606-63-2Relevant academic research and scientific papers
Novel S1P1 receptor agonists - Part 5: From amino-to alkoxy-pyridines
Bolli, Martin H.,Lescop, Cyrille,Birker, Magdalena,De Kanter, Ruben,Hess, Patrick,Kohl, Christopher,Nayler, Oliver,Rey, Markus,Sieber, Patrick,Velker, J?rg,Weller, Thomas,Steiner, Beat
, p. 326 - 341 (2016/04/19)
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.
