title: Novel S1P(1) receptor agonists--part 3: from thiophenes to pyridines.
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.
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Bolli
authors.forename: Stefan
authors.initials: S
authors.lastname: Abele
authors.forename: Magdalena
authors.initials: M
authors.lastname: Birker
authors.forename: Roberto
authors.initials: R
authors.lastname: Bravo
authors.forename: Daniel
authors.initials: D
authors.lastname: Bur
authors.forename: Ruben
authors.initials: R
authors.lastname: de Kanter
authors.forename: Christopher
authors.initials: C
authors.lastname: Kohl
authors.forename: Julien
authors.initials: J
authors.lastname: Grimont
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Cyrille
authors.initials: C
authors.lastname: Lescop
authors.forename: Boris
authors.initials: B
authors.lastname: Mathys
authors.forename: Claus
authors.initials: C
authors.lastname: Müller
authors.forename: Oliver
authors.initials: O
authors.lastname: Nayler
authors.forename: Markus
authors.initials: M
authors.lastname: Rey
authors.forename: Michael
authors.initials: M
authors.lastname: Scherz
authors.forename: Gunther
authors.initials: G
authors.lastname: Schmidt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Seifert
authors.forename: Beat
authors.initials: B
authors.lastname: Steiner
authors.forename: Jörg
authors.initials: J
authors.lastname: Velker
authors.forename: Thomas
authors.initials: T
authors.lastname: Weller
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D013876:Thiophenes