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-tolylthiazolidin-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 dosedependent 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.

Efficacy and immunomodulatory actions of ONO-4641, a novel selective agonist for sphingosine 1-phosphate receptors 1 and 5, in preclinical models of multiple sclerosis

“…We examined whether ONO-4641 decreases peripheral blood lymphocyte count similar to other S1P receptor agonists [24][25][26]. In normal Lewis rats, the peripheral blood lymphocyte count was decreased over time, and the lowest count was observed 12 h after administration in the ONO-4641-treated groups.…”

Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases

“…Oral administration of ponesimod has been shown to lead to a dose-dependent decrease of blood lymphocyte count in animals and humans [Piali et al 2011;Brossard et al 2013]. In mice with delayed-type hypersensitivity, ponesimod prevented edema formation, inflammatory cell accumulation, and cytokine release in the skin.…”

“…In mice with delayed-type hypersensitivity, ponesimod prevented edema formation, inflammatory cell accumulation, and cytokine release in the skin. In rats with adjuvant-induced arthritis, ponesimod prevented the increase in paw volume and joint inflammation [Piali et al 2011]. Treatment with ponesimod of prediabetic non obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, prevented disease development and ponesimod treatment of diabetic NOD mice induced disease remission [You et al 2013].…”

Sphingosine-1-Phosphate and Rheumatoid Arthritis: Pathological Implications and Potential Therapeutic Targets

“…Likewise, the elevated S1P levels in the synovial fluid of RA patients [48] could be responsible for the recruitment and retention of the immune infiltrates in the RA synovium. Indeed, inhibition of S1P1 down-regulated inflammatory cell accumulation in an adjuvant-induced arthritis (AIA) animal model [64]. S1P may also contribute indirectly to the recruitment and retention of inflammatory cells into RA synovium by stimulating the secretion of other chemo-attractants.…”