Upon intraperitoneal administration. A series of benzimidazole substituted anilinopyrimidines have been reported to be potent inhibitors of Lck. Compound 20 inhibited Lck with IC503 nM and inhibited phorbol A66 myristate acetate induced IL 2 production in Jurkat T cells with IC5054 nM. However, the series of compounds seemed to lack specificity against other Src family kinases and lacked desirable pharmacokinetic properties. The pyrimidopyrazine derivative, 21, is reported to be a potent Lck inhibitor with IC502 nM. The cellular activity, selectivity against other Src family of kinases, and pharmacokinetic properties of 21 were less than optimal. The anilinopyrimidine urea, 22, inhibited Lck with IC5087 nM and inhibited the hind paw swelling by 63% upon oral administration twice a day at 25 mg/kg in an adjuvant induced arthritis model in rats.
Compound 23, a close structural analog of dasatinib, a marketed kinase inhibitor drug for the treatment of chronic myelogenous leukemia, is a potent, selective, and ATP competitive inhibitor of Lck and other Src family kinases . In an ex vivo anti CD3/CD 28 induced IL 2 production model in mice, orally administered 23 reduced serum IL 2 levels Danoprevir in a dose dependent manner with ED505 mg/kg. Compound 23, which has a desirable pharmacokinetic profile in rats, was efficacious in reducing paw swelling upon oral dosing at 3 mg/kg b.i.d. in a rat adjuvant arthritis model of established disease. The 2 amino 6 aryl quinazoline derivative, 24, is a potent Lck inhibitor that is not selective against other members of Src family kinases, p38, and VEGFR2.
In a human whole blood assay, 24 inhibited the anti CD3/CD28 antibody induced IL 2 production with IC50113 nM. Compound 24 had a desirable pharmacokinetic profile in rats and was orally efficacious in reducing serum levels of IL 2 in BALB/c mice with ED50 22 mg/kg. JAK3 inhibitors The Janus kinases, JAK1, JAK2, JAK3, and Tyk2, are cytoplasmic protein tyrosine kinases that play a critical role in the cytokine receptor binding triggered signal transduction through the STAT proteins. Binding of cytokines activates the JAK kinases which phosphorylate and activate the STAT proteins. The STAT proteins form homo or heterodimers and translocate to the nucleus where they induce transcription of proinflammatory genes.
JAK3 is expressed at high levels in NK cells and normally in thymocytes, platelets, mast cells, and inducible T and B cells. JAK3, which is associated with the cytokine signaling through the γc chain of the IL 2 receptor, is critical for lymphocyte survival, differentiation, and function. In humans, mutations in JAK3 have been associated with severe combined immunodeficiency and JAK3 knockout mice are found to display defects in T, B, and NK cell development and function. Therefore, inhibition of JAK3 has potential applications in the treatment of inflammation, allergy, autoimmune disorders, and organ transplant rejection. A number of JAK3 inhibitors, such as WHI P131, WHI P154, and PNU156804, which are not highly selective against other members of the JAK family of kinases, have been reported and included in a review article. This review will focus on JAK3 inhibitors reported during 2006 2007 and the references cited here re.