p505-15 and Edema

p505-15 has been researched along with Edema* in 1 studies

Other Studies

1 other study(ies) available for p505-15 and Edema

ArticleYear
Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis.
    The Journal of pharmacology and experimental therapeutics, 2012, Volume: 340, Issue:2

    Based on genetic studies that establish the role of spleen tyrosine kinase (Syk) in immune function, inhibitors of this kinase are being investigated as therapeutic agents for inflammatory diseases. Because genetic studies eliminate both adapter functions and kinase activity of Syk, it is difficult to delineate the effect of kinase inhibition alone as would be the goal with small-molecule kinase inhibitors. We tested the hypothesis that specific pharmacological inhibition of Syk activity retains the immunomodulatory potential of Syk genetic deficiency. We report here on the discovery of (4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide acetate (P505-15), a highly specific and potent inhibitor of purified Syk (IC50 1-2 nM). In human whole blood, P505-15 potently inhibited B cell antigen receptor-mediated B cell signaling and activation (IC50 0.27 and 0.28 μM, respectively) and Fcε receptor 1-mediated basophil degranulation (IC50 0.15 μM). Similar levels of ex vivo inhibition were measured after dosing in mice (Syk signaling IC50 0.32 μM). Syk-independent signaling and activation were unaffected at much higher concentrations, demonstrating the specificity of kinase inhibition in cellular systems. Oral administration of P505-15 produced dose-dependent anti-inflammatory activity in two rodent models of rheumatoid arthritis. Statistically significant efficacy was observed at concentrations that specifically suppressed Syk activity by ∼67%. Thus specific Syk inhibition can mimic Syk genetic deficiency to modulate immune function, providing a therapeutic strategy in P505-15 for the treatment of human diseases.

    Topics: Adaptor Proteins, Signal Transducing; Animals; Arthritis, Experimental; B-Lymphocytes; Basophils; Biocatalysis; Blood; Cell Degranulation; Cell Line; Cell Line, Tumor; Cell Proliferation; Cyclohexylamines; Disease Models, Animal; Edema; Extracellular Signal-Regulated MAP Kinases; Female; Foot; Humans; Inhibitory Concentration 50; Intracellular Signaling Peptides and Proteins; Leukocytes; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Molecular Structure; Phosphorylation; Precursor Cells, B-Lymphoid; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Rats; Rats, Inbred Lew; Receptors, Antigen, B-Cell; Signal Transduction; Syk Kinase; Synovitis

2012