PH-797804

PH-797804 (CAS 586379-66-0) is an orally active, ATP-competitive inhibitor of p38 MAP kinase, with reported activity against the p38α and p38β isoforms. Its chemical name is 3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]-N,4-dimethylbenzamide, with molecular formula C22H19BrF2N2O3. The PH-797804 molecular weight is 477.30 g/mol. The PH-797804 SMILES is CNC(=O)C=1C=CC(C)=C(C1)N2C(C)=CC(OCC=3C=CC(F)=CC3F)=C(Br)C2=O. The PH-797804 chemical structure has been characterized in studies of its kinase-binding properties. PH-797804 has been investigated for its ability to inhibit inflammatory signalling and the production of pro-inflammatory mediators.

Application of PH-797804

PH-797804 is used to examine p38α-dependent signaling in inflammatory models, including effects on cytokine production, HSP27 phosphorylation, and osteoclast differentiation. Its preclinical and Phase 2 history supports comparisons across cellular, animal, and clinical data. Reported selectivity applies to the tested assays and does not exclude all off-target interactions.

In Vitro

In cell-free assays, PH-797804 inhibited p38α with an IC50 of 26 nM and a Ki of 5.8 nM. The p38β Ki was 40 nM, representing an approximately 6.9-fold difference. The reported IC50 values of 26 nM for p38α and 102 nM for p38β indicate an approximately four-fold potency difference.

In U937 cells, PH-797804 inhibited LPS-induced TNF-α production and HSP27 phosphorylation, with IC50 values of 5.9 and approximately 1.1 nM, respectively. It showed no inhibition of JNK- or ERK-pathway readouts at concentrations up to 1 μM under the reported conditions. The compound also blocked RANKL- and M-CSF-induced osteoclast formation in primary rat bone marrow cells.

In Vivo

Oral PH-797804 inhibited endotoxin-induced inflammatory responses in rats and cynomolgus monkeys. Ten days of treatment reduced joint inflammation and associated bone loss in rat and mouse arthritis models. The Pfizer PH-797804 program later included a randomized Phase 2 trial evaluating six weeks of treatment in patients with moderate to severe COPD. PH-797804 remains an investigational compound, not an approved treatment.

Biochemical and Physiological Actions

PH-797804 acts as an ATP-competitive, readily reversible p38α inhibitor and reduces p38α-dependent inflammatory signaling.

Structural studies of the PH-797804 molecular structure have characterized its binding to the p38α kinase domain, including interactions involving the pyridinone moiety and the kinase hinge. This structural information helps explain the compound's reported selectivity for p38α. The available PH-797804 structure data provide a basis for understanding its target-binding mechanism.

Features and Benefits of PH-797804

• Low-nanomolar biochemical and cellular potency.
• Selectivity assessed across kinase panels and pathway assays.
• Structurally characterized target-binding mechanism.
• Published preclinical and Phase 2 research data.

The available evidence provides a detailed framework for relating structure to pharmacological response. Before use, confirm the PH-797804 structure and purity in the product-specific CoA.