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 S1P1, one of five S1P receptors. Nonselective agonists for S1P receptors lead to blood lymphocyte count reduction. The effects of selective S1P1 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 S1P1 agonist. Ponesimod activated S1P1-mediated signal transduction with high potency (EC50 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 S1P1 using ponesimod leads to blood lymphocyte count reduction and efficacy in models of lymphocyte-mediated tissue inflammation. Immunomodulation with a rapidly reversible S1P1-selective agonist may represent a new therapeutic approach in lymphocyte-mediated autoimmune diseases.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.176487.
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ABBREVIATIONS:
- S1P
- sphingosine 1-phosphate
- S1P1–5
- S1P receptors 1–5
- DNFB
- dinitrofluorobenzene
- DTH
- delayed-type hypersensitivity
- MPO
- myeloperoxidase
- TCM
- central memory T cell
- TEM
- effector memory T cell
- TCR
- T cell receptor
- FTY720
- 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
- DMSO
- dimethyl sulfoxide
- NK
- natural killer
- PE
- phycoerythrin
- FITC
- fluorescein isothiocyanate
- IL
- interleukin
- TNF
- tumor necrosis factor
- IFN-γ
- interferon γ
- MIP-1α
- macrophage inflammatory protein 1α
- MCP-1
- monocyte chemotactic protein-1
- GRO
- growth-related oncogene
- KC
- keratinocyte-derived cytokine
- RANTES
- regulated on activation normal T cell expressed and secreted
- AIA
- adjuvant-induced arthritis
- ESR
- erythrocyte sedimentation rate
- CRP
- C-reactive protein
- CYM-5442
- 2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino) ethanol
- SEW-2871
- 5-[4-phenyl-5-(trifluoromethyl)-thiophen-2-yl]-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole
- AUY954
- 3-(((2-(2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)benzo[b]thiophen-5-yl)methyl)amino)propanoic acid
- KRP-203
- 2-amino-2-{2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl}-1,3-propanediol hydrochloride.
- Received October 25, 2010.
- Accepted February 18, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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