title: The selective sphingosine 1-phosphate receptor 1 agonist ponesimod protects against lymphocyte-mediated tissue inflammation.
abstract: Lymphocyte exit from lymph nodes and their recirculation into blood is controlled by the sphingolipid sphingosine 1-phosphate (S1P). The cellular receptor mediating lymphocyte exit is S1P(1), one of five S1P receptors. Nonselective agonists for S1P receptors lead to blood lymphocyte count reduction. The effects of selective S1P(1) agonists on blood lymphocyte count and their impact in models of lymphocyte-mediated tissue inflammation have been less investigated. We describe here the general pharmacology of ponesimod, (Z,Z)-5-[3-chloro-4-((2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolyl-thiazolidin-4-one, a new, potent, and orally active selective S1P(1) agonist. Ponesimod activated S1P(1)-mediated signal transduction with high potency (EC(50) of 5.7 nM) and selectivity. Oral administration of ponesimod to rats led to a dose-dependent decrease of blood lymphocyte count. After discontinuation of dosing, blood lymphocyte count returned to baseline within 48 h. Ponesimod prevented edema formation, inflammatory cell accumulation, and cytokine release in the skin of mice with delayed-type hypersensitivity. Ponesimod also prevented the increase in paw volume and joint inflammation in rats with adjuvant-induced arthritis. These data show that selective activation of S1P(1) using ponesimod leads to blood lymphocyte count reduction and efficacy in models of lymphocyte-mediated tissue inflammation. Immunomodulation with a rapidly reversible S1P(1)-selective agonist may represent a new therapeutic approach in lymphocyte-mediated autoimmune diseases.
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, 4123 Allschwil, Switzerland. luca.piali@actelion.com
authors.forename: Luca
authors.initials: L
authors.lastname: Piali
authors.forename: Sylvie
authors.initials: S
authors.lastname: Froidevaux
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Oliver
authors.initials: O
authors.lastname: Nayler
authors.forename: Martin H
authors.initials: MH
authors.lastname: Bolli
authors.forename: Eva
authors.initials: E
authors.lastname: Schlosser
authors.forename: Christopher
authors.initials: C
authors.lastname: Kohl
authors.forename: Beat
authors.initials: B
authors.lastname: Steiner
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001169:Arthritis, Experimental / Q000188:drug therapy; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007249:Inflammation / Q000473:pathology* / Q000517:prevention & control*; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013844:Thiazoles / Q000097:blood / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C550169:ponesimod