PH-797804 is a novel pyridinone inhibitor of p38α with IC50 of 26 nM in a cell-free assay; 4-fold more selective versus p38β and does not inhibit JNK2. Phase 2.

＞98%

Store at -20℃ for one year（Powder）；Store at 2-4℃ for two weeks；Store at -20℃ for six months after dissolution.

PH797804；PH 797804

powder

DMSO ：96 mg/mL (201.13 mM)

Ethanol ：7 mg/mL (14.66 mM)

p38α,p38β

PH-797804 blocks LPS-induced TNF-α production and p38 kinase activity in the human monocytic U937 cell line, with comparable IC50 of 5.9 nM and 1.1 nM. PH-797804 has no inhibitory effect on either the JNK pathway (c-Jun phosphorylation) or ERK pathway (ERK phosphorylation) in U937 cells at concentrations up to 1 μM. PH-797804 inhibits RANKL- and M-CSF-induced osteoclast formation in a concentration-dependent manner, with IC50 of 3 nM in primary rat bone marrow cells. IC50 values for PH-797804 against the following targets have been determined to be greater than 200 μM (unless specified): CDK2, ERK2, IKK1, IKK2, IKKi, MAPKAP2, MAPKAP3, MKK7 (>100 μM), MNK, MSK (>164 μM), PRAK, RSK2, and TBK1, which means the activity of PH-797804 is specific.

Orally dosing of PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. PH-797804 treatment for 10 days demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis. Dose-response analysis resulted in ED50 values of 0.07 mg/kg and 0.095 mg/kg in rat and cynomolgus monkeys, respectively. PH-797804 inhibits LPS-induced TNF-α, IL-6, and MK-2 activity in a dose- and concentration-dependent manner in a human endotoxin challenge model.

[1]. Heidi R. Hope et al. Anti-Inflammatory Properties of a Novel N-Phenyl Pyridinone Inhibitor of p38 Mitogen-Activated Protein Kinase: Preclinical-to-Clinical Translation JPET December 2009 vol. 331 no. 3 882-895

[2]. Li Xing e al. Structural Bioinformatics-Based Prediction of Exceptional Selectivity of p38 MAP Kinase Inhibitor PH-797804 Biochemistry, 2009, 48 (27), pp 6402-6411

[3]. Xing L, Devadas B, Devraj RV, Selness SR, Shieh H, Walker JK, Mao M, Messing D, Samas B, Yang JZ, Anderson GD, Webb EG, Monahan JB.Discovery and characterization of atropisomer PH-797804, a p38 MAP kinase inhibitor, as a clinical drug candidate.ChemMedChem. 2012 Feb 6;7(2):273-80.

[4]. Selness SR, Devraj RV, Devadas B, Walker JK, Boehm TL, Durley RC, Shieh H, Xing L, Rucker PV, Jerome KD, Benson AG, Marrufo LD, Madsen HM, Hitchcock J, Owen TJ, Christie L, Promo MA, Hickory BS, Alvira E, Naing W, Blevis-Bal R, Messing D, Yang J, Mao MK, Yalamanchili G, Vonder Embse R, Hirsch J, Saabye M, Bonar S, Webb E, Anderson G, Monahan JB.Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase.Bioorg Med Chem Lett. 2011 Jul 1;21(13):4066-71. Epub 2011 May 11. 

[5]. Xing L, Shieh HS, Selness SR, Devraj RV, Walker JK, Devadas B, Hope HR, Compton RP, Schindler JF, Hirsch JL, Benson AG, Kurumbail RG, Stegeman RA, Williams JM, Broadus RM, Walden Z, Monahan JB.Structural bioinformatics-based prediction of exceptional selectivity of p38 MAP kinase inhibitor PH-797804.Biochemistry. 2009 Jul 14;48(27):6402-11.