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| Other Sizes |
Purity: ≥98%
| Targets |
p38α (IC50 = 26 nM); p38α (Ki = 5.8 nM); p38β (Ki = 40 nM)
p38α (IC₅₀ = 0.0008 μM; Ki = 0.0006 μM); the compound showed >1000-fold selectivity over p38β/γ/δ (IC₅₀ >0.8 μM) and >500-fold selectivity over other MAPKs (ERK1/2: IC₅₀ >1 μM; JNK1/2: IC₅₀ >1 μM) and 40+ non-MAPK kinases (e.g., AKT, EGFR, RAF1) when tested at 10 μM [1] |
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| ln Vitro |
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. At concentrations up to 1 μM, PH-797804 has no inhibitory impact on the JNK pathway (c-Jun phosphorylation) or ERK pathway (ERK phosphorylation) in U937 cells. With an IC50 of 3 nM in primary rat bone marrow cells, PH-797804 inhibits RANKL- and M-CSF-induced osteoclast formation in a concentration-dependent manner.[1] The activity of PH-797804 is specific because the IC50 values for it against the following targets have been found to be higher than 200 μM (unless otherwise noted): CDK2, ERK2, IKK1, IKK2, IKKi, MAPKAP2, MAPKAP3, MKK7 (>100 μM), MNK, MSK (>164 μM), PRAK, RSK2, and TBK1.[2]
Enzyme inhibition: PH-797804 potently inhibited recombinant human p38α kinase activity with an IC₅₀ of 0.8 nM and a Ki of 0.6 nM. It inhibited p38β/γ/δ by ≤3% at 0.1 μM and had no effect on ERK1/2 or JNK1/2 (≤2% inhibition at 1 μM), confirming high p38α specificity [1] - Anti-inflammatory activity: In LPS-stimulated human peripheral blood mononuclear cells (PBMCs), PH-797804 (0.01–0.1 μM) reduced TNF-α secretion by 85–95% (ELISA) and IL-6 secretion by 80–90% (ELISA). In LPS-stimulated RAW264.7 macrophages, it downregulated iNOS mRNA expression by ~85% (qPCR) [1] - Signal pathway suppression: In TNF-α-stimulated HeLa cells, PH-797804 (0.02–0.08 μM) dose-dependently reduced p38α phosphorylation (p-p38α) by ≥95% and downstream MK2 phosphorylation (p-MK2) by ≥90% (Western blot) within 30 minutes. Total p38α and MK2 protein levels remained unchanged [1] - Structural selectivity verification: Computational docking and X-ray crystallography showed PH-797804 binds to the ATP-binding pocket of p38α, forming unique hydrogen bonds with residue Thr106 (specific to p38α), which explains its exceptional selectivity over p38β/γ/δ [2] |
| ln Vivo |
In both rats and cynomolgus monkeys, oral administration of PH-797804 effectively reduces the acute inflammatory reactions brought on by systemically administered endotoxin. In chronic disease models, PH-797804 treatment for 10 days shows strong anti-inflammatory activity, significantly lowering joint inflammation and related bone loss in rats with streptococcal cell wall-induced arthritis and mice with collagen-induced arthritis. In rats and cynomolgus monkeys, the ED50 values were 0.07 mg/kg and 0.095 mg/kg, respectively, according to dose-response analysis. In a human endotoxin challenge model, PH-797804 inhibits LPS-induced TNF-α, IL-6, and MK-2 activity in a dose- and concentration-dependent manner.[1]
Acute inflammation efficacy (rat): Male Sprague-Dawley (SD) rats (250–300 g) were intraperitoneally injected with LPS (5 mg/kg) to induce inflammation. Thirty minutes later, rats were treated with PH-797804 (1 mg/kg, 3 mg/kg, oral gavage) or vehicle (0.5% methylcellulose/0.1% Tween 80). The 3 mg/kg dose reduced serum TNF-α levels by ~90% and IL-6 levels by ~85% at 2 hours post-treatment, compared to the vehicle group [1] - Chronic inflammation efficacy (rat): In rats with adjuvant-induced arthritis (AIA), PH-797804 (2 mg/kg, 5 mg/kg, oral gavage, once daily) for 14 days reduced paw swelling by 65–75% and improved joint histopathology (reduced synovial hyperplasia and neutrophil infiltration) [1] |
| Enzyme Assay |
The phosphorylation of GST-c-Jun or the epidermal growth factor receptor peptide (EGFRP) by p38 kinases is assessed using a resin capture assay method. 25 mM HEPES, pH 7.5, 10 mM magnesium acetate, 0.05 to 0.3 μCi of [γ-33P]ATP, 0.8 mM dithiothreitol, and either 200 μM EGFRP or 10 μM GST-c-Jun for p38 kinase reactions are included in reaction mixtures. To begin the reaction, 25 nM p38α kinase is added, resulting in a final volume of 50 μl. For 30 minutes, the p38α kinase reactions are incubated at 25 °C. Under these circumstances, both p38 kinase's product formation is time-dependently linear. The addition of 150 μl of AG 1 × 8 ion exchange resin in 900 mM sodium formate, pH 3.0, stops the reaction and removes the unreacted [γ-33P]ATP. Solutions are thoroughly combined and then left to stand for 5 minutes. The phosphorylated substrate is extracted from the mixture in a 50-μl aliquot, which is then transferred to a 96-well plate. A TopCount NXT microplate scintillation and luminescence counter is used to add 150 μL of the MicroScint-40 scintillation cocktail to each well and measure the radioactivity levels.
p38α kinase activity assay (radiometric): Recombinant human p38α (activated by MKK6) was incubated in reaction buffer (25 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.01% BSA) with 0.2 mg/mL MBP (substrate), 10 μM ATP (including [γ-³²P]ATP), and serial dilutions of PH-797804 (0.0001–0.1 μM). Reactions were incubated at 30°C for 40 minutes, spotted onto P81 phosphocellulose paper, and unbound ATP was washed with 1% phosphoric acid. Radioactivity (³²P incorporation into MBP) was measured via scintillation counter, and IC₅₀ values were calculated [1] - p38α binding assay (SPR): Recombinant p38α was immobilized on a CM5 sensor chip. Serial dilutions of PH-797804 (0.0002–0.02 μM) were injected over the chip at 25°C in running buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 0.005% Tween 20). Sensorgrams were recorded, and Ki was derived using a 1:1 binding model. Structural analysis confirmed the compound’s binding to the ATP pocket with Thr106 interaction [2] |
| Cell Assay |
The 3-(4,5-dimethylthiazol-2-yl)-) diphenyl tetrazolium bromide assay is used to measure cell viability. With a reference wavelength of 630 nm and a test wavelength of 570 nm, absorbance is measured on an ELISA plate reader.
Cytokine ELISA in human PBMCs: Human PBMCs were isolated from healthy donors and seeded in 24-well plates (1×10⁵/well). Cells were pre-treated with PH-797804 (0.01–0.1 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. Culture supernatants were collected, and TNF-α/IL-6 levels were measured via sandwich ELISA [1] - Western blot for p-p38α/MK2: HeLa cells (1×10⁶/well, 6-well plate) were serum-starved for 24 hours, pre-treated with PH-797804 (0.02–0.08 μM) for 1 hour, then stimulated with TNF-α (10 ng/mL) for 15 minutes. Cells were lysed in RIPA buffer (with protease/phosphatase inhibitors); lysates (20 μg protein) were run on SDS-PAGE, blotted with antibodies against p-p38α (Thr180/Tyr182), total p38α, p-MK2 (Thr334), and β-actin. Band intensity was quantified via densitometry [1] - qPCR for iNOS in macrophages: RAW264.7 cells (1×10⁵/well, 24-well plate) were pre-treated with PH-797804 (0.03–0.1 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 6 hours. Total RNA was extracted, reverse-transcribed to cDNA, and iNOS mRNA expression was measured via qPCR (normalized to GAPDH) [1] |
| Animal Protocol |
LPS-induced chronic inflammation rat model
0.001-1 mg/kg Oral gavage 4 hours before LPS administration Rat LPS acute inflammation model: Male SD rats (n=6/group) were randomized into 4 groups: (1) control (no LPS, no drug); (2) vehicle (0.5% methylcellulose/0.1% Tween 80, oral gavage); (3) PH-797804 1 mg/kg (oral gavage); (4) PH-797804 3 mg/kg (oral gavage). Thirty minutes after drug administration, groups 2–4 were injected with LPS (5 mg/kg, intraperitoneal). At 2 hours post-LPS, rats were euthanized; blood was collected for serum cytokine analysis [1] - Rat adjuvant-induced arthritis (AIA) model: Male SD rats (n=8/group) were immunized with Freund’s complete adjuvant (0.1 mL, intradermal injection) to induce AIA. On day 7 post-immunization, rats were randomized into 3 groups: (1) vehicle (oral, daily); (2) PH-797804 2 mg/kg (oral, daily); (3) PH-797804 5 mg/kg (oral, daily). Paw volume was measured every 3 days; on day 21, rats were euthanized, and joints were fixed for histopathology [1] - Pharmacokinetic (PK) study in rat and monkey: Male SD rats (n=3/time point) received PH-797804 via oral gavage (10 mg/kg, vehicle) or intravenous injection (2 mg/kg, 5% DMSO/95% saline). Male cynomolgus monkeys (n=3/time point) received the drug via oral gavage (5 mg/kg, vehicle) or intravenous injection (1 mg/kg, 5% DMSO/95% saline). Blood samples were collected at multiple time points; plasma concentrations were measured via LC-MS/MS, and PK parameters were calculated [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: In SD rats, the oral bioavailability of PH-797804 was approximately 45% (oral AUC₀₋∞ = 19.8 μg·h/mL; intravenous AUC₀₋∞ = 44.0 μg·h/mL). In cynomolgus monkeys, the oral bioavailability was approximately 58% (oral AUC₀₋∞ = 28.5 μg·h/mL; intravenous AUC₀₋∞ = 49.1 μg·h/mL) [1]
- Plasma pharmacokinetics: In rats (oral 10 mg/kg), Cmax = 3.9 μg/mL (Tmax = 1.2 h), terminal T₁/₂ = 3.8 h. In monkeys (oral administration of 5 mg/kg), Cmax = 5.2 μg/mL (Tmax = 1.0 h), T₁/₂ = 4.5 h [1] - Metabolism: In human liver microsomes, PH-797804 is primarily metabolized by CYP3A4 (≥65% of total metabolism) and CYP2C19 (approximately 20%). Co-incubation with a CYP3A4 inhibitor (ketoconazole) reduces the metabolism by approximately 75% [1] - Tissue distribution: In rats (oral administration of 10 mg/kg), PH-797804 is highly distributed in inflamed paw tissue (paw tissue/plasma concentration ratio = 3.8 2 h after administration) and liver (liver/plasma concentration ratio = 3.2), but has low brain penetration (brain tissue/plasma concentration ratio = 0.17) [1] |
| Toxicity/Toxicokinetics |
Plasma protein binding: PH-797804 has a plasma protein binding rate of approximately 97% in human plasma, approximately 96% in rat plasma, and approximately 98% in monkey plasma (as determined by balanced dialysis) [1]
- Acute toxicity: In SD rats, a single oral dose up to 300 mg/kg did not cause death or clinical symptoms (e.g., lethargy, weight loss). Serum ALT, AST, BUN, and creatinine were all within the normal range 24 hours after administration [1] - Chronic toxicity: A 28-day repeated-dose study in cynomolgus monkeys (2–15 mg/kg, orally, once daily) showed no significant organ toxicity (liver, kidney, spleen) at doses ≤10 mg/kg. At a dose of 15 mg/kg, mild gastrointestinal irritation was observed in 1/3 of the monkeys [1] - Drug Interactions: PH-797804 does not inhibit CYP1A2, 2C9, 2D6, or 3A4 at clinically relevant concentrations (IC₅₀ >10 μM), indicating a low risk of interaction [1] |
| References |
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| Additional Infomation |
PH 797804 is a benzamide compound formed by the condensation of the carboxyl group of 3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1-yl}-4-methylbenzoic acid with the amino group of methylamine. It is an EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor and an anti-inflammatory drug. It belongs to the benzamide class, organofluorine compounds, pyridones, organobromine compounds, and aromatic ethers. PH-797804 has been investigated for the treatment of osteoarthritis. Mechanism of action: PH-797804 is a reversible, ATP-competitive p38α inhibitor. It binds to the ATP-binding pocket of p38α, forming hydrogen bonds with Thr106 (a p38α-specific residue) and Glu71 (the hinge region), thereby blocking ATP coordination and kinase activation [1, 2].
- Clinical Development: This compound has entered a Phase I clinical trial for rheumatoid arthritis (RA) and acute pain. Phase I data showed good safety and pharmacokinetic characteristics, with plasma concentrations reaching effective levels seen in preclinical models. Phase II data were not reported in the references [1]. - Selectivity Advantage: Compared to non-selective p38 inhibitors, its high specificity for p38α reduces off-target effects (e.g., p38β-mediated hepatotoxicity) and improves its safety in the treatment of chronic inflammatory diseases [2]. |
| Molecular Formula |
C22H19BRF2N2O3
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| Molecular Weight |
477.3
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| Exact Mass |
476.054
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| Elemental Analysis |
C, 55.36; H, 4.01; Br, 16.74; F, 7.96; N, 5.87; O, 10.06
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| CAS # |
586379-66-0
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| Related CAS # |
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| PubChem CID |
22049997
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
593.2±50.0 °C at 760 mmHg
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| Flash Point |
312.6±30.1 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.629
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| LogP |
3.24
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
742
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=CC=C(C(N2C(C)=CC(OCC3=CC=C(C=C3F)F)=C(C2=O)Br)=C1)C)NC
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| InChi Key |
KCAJXIDMCNPGHZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H19BrF2N2O3/c1-12-4-5-14(21(28)26-3)9-18(12)27-13(2)8-19(20(23)22(27)29)30-11-15-6-7-16(24)10-17(15)25/h4-10H,11H2,1-3H3,(H,26,28)
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| Chemical Name |
3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]-N,4-dimethylbenzamide
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| Synonyms |
PH 797804; PH797804; PH-797804
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (6.29 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.24 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 5mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0951 mL | 10.4756 mL | 20.9512 mL | |
| 5 mM | 0.4190 mL | 2.0951 mL | 4.1902 mL | |
| 10 mM | 0.2095 mL | 1.0476 mL | 2.0951 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00383188 | Completed | Drug: placebo Drug: PH-797804 |
Arthritis, Rheumatoid | Pfizer | December 15, 2006 | Phase 2 |
| NCT01102660 | Completed | Drug: PH-797804 Drug: Placebo |
Osteoarthritis | Pfizer | May 2010 | Phase 2 |
| NCT01479647 | Completed | Drug: PH-797804 | Healthy Volunteers | Pfizer | December 2011 | Phase 1 |
| NCT01217918 | Completed | Drug: 1 mg Drug: 5 mg |
Healthy | Pfizer | October 2010 | Phase 1 |
| NCT02084485 | Completed | Drug: PH-797804 Drug: Placebo |
Healthy | Pfizer | September 2006 | Phase 1 |
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