title: Novel S1P1 receptor agonists - Part 4: Alkylaminomethyl substituted aryl head groups.
abstract: In a previous communication we reported on the discovery of alkylamino pyridine derivatives (e.g. 1) as a new class of potent, selective and efficacious S1P1 receptor (S1PR1) agonists. However, more detailed profiling revealed that this compound class is phototoxic in vitro. Here we describe a new class of potent S1PR1 agonists wherein the exocyclic nitrogen was moved away from the pyridine ring (e.g. 11c). Further structural modifications led to the identification of novel alkylaminomethyl substituted phenyl and thienyl derivatives as potent S1PR1 agonists. These new alkylaminomethyl aryl compounds showed no phototoxic potential. Based on their in vivo efficacy and ability to penetrate the brain, the 5-alkyl-aminomethyl thiophenes appeared to be the most interesting class. Potent and selective S1PR1 agonist 20e, for instance, maximally reduced the blood lymphocyte count (LC) for 24 h after oral administration of 10 mg/kg to rat and its brain concentrations reached >500 ng/g over 24 h.
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Electronic address: cyrille.lescop@actelion.com.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Lescop
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Claus
authors.initials: C
authors.lastname: Müller
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Boris
authors.initials: B
authors.lastname: Mathys
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Birker
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Ruben
authors.initials: R
authors.lastname: de Kanter
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kohl
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Nayler
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Rey
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sieber
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Steiner
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weller
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Bolli
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D011725:Pyridines; D049349:Receptors, Lysosphingolipid; C023666:pyridine
keywords: Aminomethyl benzene; Aminomethyl pyridine; Aminomethyl thiophene; Immunomodulator; Lymphocyte count; Phototoxicity; S1P(1) receptor agonist