title: Novel S1P1 receptor agonists - Part 5: From amino-to alkoxy-pyridines.
abstract: 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.
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Electronic address: martin.bolli@actelion.com.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Bolli
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Lescop
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Birker
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Ruben
authors.initials: R
authors.lastname: de Kanter
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kohl
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Nayler
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Rey
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sieber
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Velker
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weller
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Steiner
mesh_terms: D000818:Animals; D008297:Male; D066244:Proton Magnetic Resonance Spectroscopy; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D011725:Pyridines; D049349:Receptors, Lysosphingolipid
keywords: Immunomodulation; In vitro phototoxicity; Light extinction; Lymphocyte count; Pyridine; S1P(1) receptor agonist