Compound 6 inhibited LPS induced TNF production in human PBMCs with IC50_50 nM. Oral administration of 0. 3C3 mg/kg of compound 6 inhibited the arachidonic acid induced ear edema in mice in the dose dependent method. The antiinflammatory action of 6 at 1 mg/kg oral dose in this model was superior to that of dexamethasone hts screening at 0. 3 mg/kg oral dose. The oral bioavailability of 6 in rats was 60% with lower clearance. Compound 7 has become reported for being a potent, ATP competitive, and moderately selective inhibitor of IKK2 with Ki_2 nM. The compound inhibited the cytokines along with other inflammatory mediators inside a number of cells on induction. Compound 7 had superior bioavailability in rats and mice and showed beneficial effects in animal versions of allergy, lung inflammation, edema, and delayed type hypersensitivity.
Structural modification of SC 415, a recognized weak but selective IKK2 inhibitor, has yielded compound 8 and analogs with modest IKK2 inhibitory potency. Compound 8, with IC50_333 small molecule library screening nM for inhibition of IKK2, inhibited IL 8 production in IL 1B stimulated synovial fibroblasts derived from rheumatoid arthritis individuals with IC50_832 nM. A structurally associated compound TPCA 1 has become reported to be an ATP aggressive and selective inhibitor of IKK2 with IC50_18 nM. The manufacturing of cytokines like TNF, IL 6, and IL 8 induced by LPS in human PBMCs was inhibited by TPCA 1 with IC50_ 170 320 nM. A 20 mg/kg oral dose of TPCA 1 administered twice each day to mice considerably decreased the clinical score and ailment severity within a collagen induced arthritis model.
Compound 9, an isomer of TPCA 1, continues to be reported for being a potent inhibitor of IKK2 Skin infection with IC50_63 nM and 100 fold selective over IKK1. In PBMCs, the LPS induced TNF manufacturing was inhibited by 9 with IC50 _ 400 nM. The compound showed lower in vitro metabolic clearance in rat hepatocytes, very low in vitro plasma protein binding, and excellent oral bioavailability. An anilinopyrimidine derivative, ten, continues to be reported to get a potent IKK2 inhibitor with IC50_40 nM. In human vascular endothelial cells, 10 inhibited the TNF induced expression with the adhesion molecules ICAM 1 and VCAM 1 with IC50_300 nM. Administration of 30 mg/kg oral dose of 10 inhibited TNF release by 75% upon LPS challenge in rats. Compound ten exhibited anti inflammatory action in the thioglycollate induced peritonitis model in mice.
At a dose of ten mg/kg s. c., ten inhibited neutrophil extravasation by 50% on this model. SPC 839, whose framework is undisclosed, has become reported to become a potent and selective IKK2 inhibitor by using a major oral anti inflammatory exercise in an adjuvant induced arthritis model in rats. The compound has become KK-16 IKK Inhibitors licensed to Serono as well as the publications from this business disclose this compound as AS602868 and that is an anilinopyrimidine derivative. PS 1145 has become reported for being a potent IKK2 inhibitor with IC50_100 nM.
Jian Dan