Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine kinase

Inflammopharmacology. 2011 Apr;19(2):75-87. doi: 10.1007/s10787-010-0060-6. Epub 2010 Oct 11.

Abstract

Pro-inflammatory cytokines like TNF-α activate sphingosine kinase (SK). Therefore, inhibition of SK is a potential molecular target for the treatment of rheumatoid arthritis.

Aims: The primary goal of this study was to assess the efficacy of ABC249640 (a selective SK-2 inhibitor) in two models of rodent arthritis. A secondary goal was to evaluate the pharmacological profile of ABC294640, when given in combination with methotrexate.

Methods: The efficacy of ABC294640 was determined by paw diameter/volume measurements, histological evaluations, and micro-CT analyses.

Results: ABC294640 attenuated both collagen-induced arthritis in mice, as well as adjuvant-induced arthritis in rats. With the adjuvant arthritis model, the prophylactic efficacy profile of ABC294640 was similar to indomethacin. Of note, ABC294640 reduced the bone and cartilage degradation, associated with adjuvant-induced arthritis. Rats treated with a suboptimal dose of MTX (50 μg/kg/day) in combination with ABC249640 (100 mg/kg/day) had better anti-arthritis effects in the adjuvant model, than treatment with either agent alone.

Conclusion: Our results suggest that ABC249640 is an orally available drug candidate with a good pre-clinical efficacy profile for the prevention and/or treatment of RA.

MeSH terms

  • Adamantane / administration & dosage
  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacology
  • Adamantane / therapeutic use
  • Administration, Oral
  • Animals
  • Ankle / pathology
  • Ankle Joint / drug effects
  • Ankle Joint / pathology
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / pathology
  • Arthritis, Experimental / prevention & control*
  • Body Weight / drug effects
  • Drug Therapy, Combination
  • Edema / pathology
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Foot / pathology
  • Indomethacin / administration & dosage
  • Indomethacin / pharmacology
  • Indomethacin / therapeutic use
  • Inflammation / pathology
  • Methotrexate / administration & dosage
  • Methotrexate / pharmacology
  • Methotrexate / therapeutic use
  • Mice
  • Mice, Inbred DBA
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Pyridines / administration & dosage*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Rats
  • Rats, Inbred Lew
  • Splenomegaly / chemically induced
  • Splenomegaly / drug therapy
  • Splenomegaly / pathology
  • Splenomegaly / prevention & control
  • X-Ray Microtomography

Substances

  • Enzyme Inhibitors
  • Pyridines
  • 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Adamantane
  • Indomethacin
  • Methotrexate