Young Boys, Job Combined With cdk1 inhibitor Cell Cycle inhibitor

The oxindoles 11a and 11b are already reported to inhibit Syk with IC50_20 and 145 nM, respectively.

In an ovalbumin induced airway inflammation model from the rat, the efficacy of BAY 61 3606, at a dose of 30 mg/kg, b. i. d., in suppressing the accumulation cdk1 inhibitor of eosinophils in BAL fluid was similar to that of 0. 3 mg/kg po, b. i. d., of dexamethasone. The less than adequate pharmacokinetic profile of BAY 61 3606 contributed to the need for the high dose in rats for efficacy of this potent inhibitor of Syk. Compound 13 has been reported to be a potent and selective Syk inhibitor with IC50 _ 41 nM. The compound inhibited the degranulation of RBL 2H3 cells with IC50_460 nM and inhibited the IgE induced passive cutaneous anaphylaxis reaction in mice with ED50_13. 2 mg/kg s. c. R112 and R406, two structurally related analogs, have been reported to be potent, selective, and ATP competitive inhibitors of Syk.

In healthy human volunteers, orally administered R406 was well tolerated, exhibited desirable pharmacokinetic properties, and inhibited baso phil activation and degranulation induced ex vivo by IgE in a dose dependent manner. The lymphocyte specific kinase, belonging to the Src family of tyrosine kinases, is expressed in T cells and natural killer cells and is NSCLC responsible for the activation of and signaling through the T cell receptor. Activation of this cascade results in the upregulation of inflammatory cytokines such as IL 2 and interferon, and ultimately in the activation and proliferation of T lymphocytes to generate an immune response. Therefore, inhibition of Lck is likely to elicit an immunosuppressive effect that could be useful in the treatment of T cell mediated diseases like rheumatoid arthritis, inflammatory bowel disease, psoriasis, and organ graft rejection.

The pharmacokinetic profile of 14 was determined to be modest. A series of 2,3 diaryl furopyrimidines have been reported to be modestly selective cdk1 inhibitor Lck inhibitors. Compound 15 inhibited Lck with IC50 _ 98 nM and inhibited anti CD3/CD 28 induced secretion of IL 2 in T cells isolated from human peripheral blood lymphocytes with IC50_430 nM.