Whatever They Said About Aurora B inhibitor BI-1356 Is simply Dead Wrong

The anilinopyrimidine urea, 22, inhibited Lck with IC50_87 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.

In an ex vivo anti CD3/CD 28 induced IL 2 production model in mice, orally administered 23 reduced BI-1356 serum IL 2 levels in a dose dependent manner with ED50_5 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 IC50_113 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.

In humans, mutations in JAK3 have been associated with severe combined immunodeficiency and JAK3 knockout mice are found to display BI-1356"href="http://www.selleckchem.com/products/linagliptin-bi-1356.html">BI-1356 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 refer to the inhibitors reported earlier. A number of JAK3 inhibitors have been disclosed in an abstract, manuscript, or at scientific meetings without disclosing their structure and/or pharmacology profile, such inhibitors are not covered in this review.

The lower potency of PF 956980 in this assay was attributed to its higher protein binding. BI-1356"href="http://www.selleckchem.com/products/linagliptin-bi-1356.html">BI-1356 In a DTH test in mice, PF 956980 when dosed by an i. v. infusion inhibited the sheep red blood cell induced paw swelling with EC50_5 mg/kg.