Cabozantinib Capecitabine Developers Unite!

In lipopolysaccharide stimulated THP 1 cells, the expression of proinflammatory cytokines such as interleukin 1B, IL 6, and tumor necrosis element alpha was inhibited with IC50_15 uM.

A structurally relevant, imidazo thieno pyrazine derivative, 4, is reported to inhibit IKK2 with IC50_13 nM and IKK1 with IC50_390 nM. Cabozantinib A 10 mg/kg oral administration of 4 to mice, 1 h prior to LPS challenge, inhibited TNF levels by 50%. However, administration of 4, 4 h prior to LPS challenge, did not inhibit TNF levels, indicating that the compound has a short half life. A series of 2 anilino 4 arylpyrimidines such as compound 5 have been reported to be potent IKK2 inhibitors with IC50_11 nM for compound 5. The authors have not disclosed cellular and in vivo activity profiles of the compounds and have attempted to explain the SAR using a homology model of IKK2 and using quantitative structureactivity relationship models.

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. Capecitabine 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. A structurally related compound TPCA 1 has been reported to be an ATP competitive and selective inhibitor of IKK2 with IC50_18 nM. The production of cytokines such as TNF, IL 6, and IL 8 induced by LPS in human PBMCs was inhibited by TPCA 1 with IC50_ 170 320 nM.

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. PS 1145 has been reported to be a potent IKK2 inhibitor with IC50_100 nM.