Ever Taken A Crack At An AG-1478 ALK Inhibitor You Are Happy With?

Compound 6 inhibited LPS induced TNF production in human PBMCs with IC50_50 nM. Oral administration of 0. 3?3 mg/kg of compound 6 inhibited the arachidonic acid induced ear edema in mice within a dose dependent manner.

The oral bioavailability of 6 in rats was 60% with lower clearance. AG-1478 Compound 7 has been reported to be a potent, ATP competitive, and moderately selective inhibitor of IKK2 with Ki_2 nM. The compound inhibited the cytokines and other inflammatory mediators in a variety of cells upon induction. Compound 7 had good bioavailability in rats and mice and showed beneficial effects in animal models of allergy, lung inflammation, edema, and delayed type hypersensitivity. Structural modification of SC 415, a known weak but selective IKK2 inhibitor, has yielded compound 8 and analogs with modest IKK2 inhibitory potency. Compound 8, with IC50_333 nM for inhibition of IKK2, inhibited IL 8 production in IL 1B stimulated synovial fibroblasts derived from rheumatoid arthritis patients with IC50_832 nM.

An anilinopyrimidine derivative, 10, has been reported to be a potent IKK2 inhibitor with IC50_40 nM. In human vascular endothelial cells, 10 inhibited the TNF induced expression of the adhesion molecules ICAM 1 and VCAM 1 with IC50_300 nM. VEGF Administration of 30 mg/kg oral dose of 10 inhibited TNF release by 75% upon LPS challenge in rats. Compound 10 exhibited anti inflammatory activity in a thioglycollate induced peritonitis model in mice. At a dose of 10 mg/kg s. c., 10 inhibited neutrophil extravasation by 50% in this model. SPC 839, whose structure is undisclosed, has been reported to be a potent and selective IKK2 inhibitor with a significant oral anti inflammatory activity in an adjuvant induced arthritis model in rats. The compound has been licensed to Serono and the publications from this company disclose this compound as AS602868 which is an anilinopyrimidine derivative.

A variety of experimental evidence points to the potential use of Syk inhibitors in the treatment of various autoimmune disorders. Figure 2 shows the structure of Syk inhibitors discussed below.