3-(4-chlorophenyl)-adamantane-1-carboxylic-acid-(pyridin-4-ylmethyl)amide and Body-Weight

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

Topics: Adamantane; Administration, Oral; Animals; Ankle; Ankle Joint; Arthritis, Experimental; Body Weight; Drug Therapy, Combination; Edema; Enzyme Inhibitors; Female; Foot; Indomethacin; Inflammation; Methotrexate; Mice; Mice, Inbred DBA; Phosphotransferases (Alcohol Group Acceptor); Pyridines; Rats; Rats, Inbred Lew; Splenomegaly; X-Ray Microtomography

Activation of sphingosine kinase (SK) is a key response to many inflammatory processes. The present studies test the hypothesis that an orally available SK inhibitor, ABC294640, would be effective in rodent models of Crohn's disease.. Trinitrobenzene sulfonic acid (TNBS) was administered rectally to mice and rats. Rats were treated with ABC294640 orally alone or in combination with olsalazine and disease progression was monitored.. For both rodent species, treatment with ABC294640 attenuated disease progression. Colon samples from the ABC294640-treated animals had improved histology and cytokine parameters when compared with vehicle-treated animals. The expression of SK was similarly increased in TNBS-treated animals and in human colon tissue specimens from inflammatory bowel disease patients relative to normal, control patients.. Sphingosine kinase may be a critical mediator of colonic damage during intestinal inflammation, and pharmacologic inhibitors of this enzyme may prove useful in the treatment of Crohn's disease.

Topics: Adamantane; Aminosalicylic Acids; Animals; Body Weight; Colon; Crohn Disease; Disease Models, Animal; Drug Therapy, Combination; Enzyme Inhibitors; Epithelial Cells; Female; Gastrointestinal Agents; Humans; Interleukin-1beta; Leukocytes; Male; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; Phosphotransferases (Alcohol Group Acceptor); Prednisolone; Pyridines; Rats; Rats, Sprague-Dawley; Treatment Outcome; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha