Drugs in Clinical Pipeline: PH-797804 | MAPK14 (p38 alpha) Kinase Inhibitor | Anti-inflammatory Drugs

PH-797804 [(aS)-3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl}-N,4-dimethylbenzamde] is an oral, highly potent, selective and metabolically stable p38 mitogen-activated protein (MAP) kinase (MAPK14) inhibitor. In the kinase activity assay PH-797804 inhibits recombinant p38α kinase with an IC₅₀ value of 16 nM, showing 110-fold selectivity over p38β kinase (IC₅₀ value of 107 nM) [1, 2].

Structure of PH-797804 and its atropisomers 

Chemically, PH-797804 is diarylpyridinone scaffold bearing inhibitor of p38 mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS). Computational studies first proposed the existence two atropisomers due to the steric bulk of the pyridinone carbonyl and the 6- and 6’-methyl substituents of racemic molecule. Chiral chromatography of racemate resolved into two atropisomers, PH-797804 (aS) and PH-797805 (aR).

The serine-threonine kinase p38 has been shown to play a role in the biosyntheses of several key pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β). In human cells PH-797804 blocks inflammation-induced production of cytokines. After oral dosing, PH-797804 demonstrates robust anti-inflammatory activity in chronic disease models, significantly decreasing both joint inflammation and associated bone loss. In clinical studies PH-797804 decreased TNFα and IL-6 production in a dose-dependent manner.

The excellent oral efficacy in preclinical models of inflammation coupled with a favorable pharmacokinetic (low clearance) and selectivity profile enabled the selection of PH-797804 as an appropriate candidate to interrogate the therapeutic potential of p38 as a molecular target.

The last available information for this amazing and structurally unique molecule reports that PH-797804 reached phase II clinical studies in chronic obstructive pulmonary disease (COPD), musculoskeletal pain, neuropathic pain, rheumatoid arthritis as a therapeutic agent for inflammation mediated diseases. But, for reasons unknown it has been since discontinued.

MAPK14 (p38α) as a Drug Traget for Inflammation:

The serine-threonine kinase p38 has been shown to play a role in the biosyntheses of several key pro-inflammatory cytokines such as tumor necrosis factor- α (TNFα) and interleukin-1β (IL-1β).1The p38 MAP kinase family consists of four isoforms: α, β, γ, and δ . These kinases show a high degree of sequence homology, with 60 to 75% overall sequence identity and nearly 90% within the kinase domain. The α and β isoforms are ubiquitously expressed, with the α isoform being the better characterized in terms of its role in inflammation.

Other isoforms have no major role in inflammation with few reports supporting the role of β in management of pain. The γ and δ isoforms are expressed in a tissue-restricted manner, with γ expressed in skeletal muscle and δ expressed in lungs, kidneys, testis, pancreas, and intestines.

Due to the apparent role of p38α kinase in inflammation, its therapeutic potential has been extensively studied. Several small-molecule inhibitors of p38 kinase have been generated and characterized. Side effects commonly reported included skin rash, elevated liver enzymes, and gastrointestinal disorders. Derived from diverse chemical templates, these clinical candidates displayed broad kinase selectivity patterns. Therefore, the adverse effects observed may be associated with the promiscuity of the compounds, but not based on the mechanism of p38α inhibition.

Mechanism of Action in PH-797804:

PH-797804 is an orally available, small molecule, selective and nanomolar inhibitor of MAPK14 (p38α) kinase. It is resolved from a racemic mixture as the more potent atropisomer (aS).

The existence of atropisomers for PH-797804 was first proposed by molecular modeling and subsequently confirmed by experiments. Due to steric constraints imposed by the pyridinone carbonyl group and the 6- and 6’-methyl substituents of PH-797804, rotation around the connecting bond of the pyridinone and the N-phenyl ring is restricted. Density functional theory predicted a remarkably high rotational energy barrier of greater than 30 kcal/mol. Such an energy barrier corresponds to a half-life of more than one hundred years at room temperature; giving rise to discrete conformational spaces for the N-phenylpyridinone group, and as a result, birth to two atropic isomers that do not interconvert under ambient conditions.

The two isomers were subsequently identified and separated by chiral chromatography. IC₅₀ values from p38α kinase assays confirm that one atropisomer is more than 100-fold more potent than the other. It was ultimately confirmed by small-molecule X-ray diffraction that the more potent atropisomer, PH-797804, is the aS isomer of the racemic pair. Computational studies too had predicted the atropic S (aS) isomer binds favorably, the opposite aR (PH-797805) isomer incurs significant steric interference with p38a kinase.

Moreover, PH-797804 shows complete selectivity over JNK2 kinase (IC₅₀ more than 200 uM) [1, 2].

Dosages and Approvals:

PH-797804 (Trademark: -) is being developed by Pfizer for pain management in chronic obstructive pulmonary disease, musculoskeletal pain, neuropathic pain, rheumatoid arthritis. Further trials have been discontinued for these conditions.

Reported Activities for PH-797804: (racemic, aS, aR)

IC₅₀ (Inhibition of P38α kinase activity) = 26 ± 8, 16.4, 1760 nM

IC₅₀ (Inhibition of P38β kinase activity) = 102 ± 38, 107, 5240 nM

K_i (P38α binding assay) = 5.8 ± 0.3, 3.9, 183 nM

Summary

Common name: PH-797804;  PH 797804; PH797804

Trademarks: -

Molecular Formula: C22H19BrF2N2O3

CAS Registry Number: 1358027-80-1 (aS)

CAS Name: (aS)-3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl}-N,4-dimethylbenzamde

Molecular Weight: 477.30

SMILES:FC1=CC=C(COC(C=C(C)N2C3=CC(C(NC)=O)=CC=C3C)=C(Br)C2=O)C(F)=C1

InChI Key: KCAJXIDMCNPGHZ-UHFFFAOYSA-N

InChI: 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)

Mechanism of Action: Mitogen-Activated Protein Kinase 14 (MAPK14) Kinase; Kinase Inhibitor; p38α Inhibitor

Activity: Management of Pain; Anti-inflammatory Agents

Status: Under Phase Trials; Discontinued

Chemical Class: Small molecules; Amide containing; N-Phenyl Pyridinone compound; Fluoro compound; Bromo containing

Originator: Pfizer

PH-797804 Synthesis

Bioorg Med Chem Lett 2011, 21(13), 4066 – 4071: The article reports an an enzymatic resolution using a bacillus protease mediated hydrolysis of the ester intermediate. Non-selective hydrolysis could be avoided by maintaining the pH at or below 9.1. Upon completion of the selective hydrolysis (monitored by liquid chromatography and a chiral stationary phase) the pH was adjusted to 6 to precipitate the ester. The slurry was filtered and the filtrate was acidified to a pH of 3.6 to generate an additional precipitate; filtration afforded the acid. Activation of acid with oxalyl chloride followed by reaction with methyl amine generated the amide intermediate. Alkylation of amide with 2,4-difluorobenzyl bromide provided (-) atropisomer  [PH-797804]. The optical rotation of the PH-797804 generated via this route was consistent with that observed for the chromatographically separated material.

Synthesis of PH-797804

Identifications:

1H NMR (Estimated) for PH-797804

Experimental: To be filled later.

Sideeffects: The most frequently reported adverse events (AEs) in COPD trials were exacerbation, rash and nasopharyngitis. Rash was the most frequently reported treatment-related adverse event. All reported rashes resolved on cessation of treatment. Three patients (6 mg PH-797804) experienced serious adverse events considered to be treatment related by the investigator; two had gastrointestinal (GI) haemorrhages (one with a history of GI complications including past GI bleed, partial gastrectomy and heavy alcohol intake). The other had been self-medicating with over-the-counter aspirin.

There were no significant trends in mean ECG parameters, although there was an increase in the percentage of patients with changes from baseline in QT interval corrected for heart rate using Fridericia’s formula.

Others:

1. PH-797804 (aS) is the more potent atropisomer in vitro and in vivo.

2. Density functional theory predicted a remarkably high rotational energy barrier, projecting a low interconversion rate that supports pharmaceutical development of a single enantiomer of higher potency (PH-797804) as the drug candidate.

3. The atropic S isomer (aS)-PH-797804 binds favorably, the opposite (aR)-PH- 797805 isomer incurs significant steric interference with p38a kinase.

4. The separate atropisomers are stable at ambient conditions during storage. The compounds were stored either in the solid state or as solutions in ethanol or acetonitrile. No loss in optical purity was observed at room temperature for at least three weeks.

References:

1. Xing, L.; et. al. Discovery and characterization of atropisomer PH-797804, a p38 MAP kinase inhibitor, as a clinical drug candidate. ChemMedChem 2012, 7(2), 273 - 280. (FMO)

2. Selness, S. R.; et. al. Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase. Bioorg Med Chem Lett 2011, 21(13), 4066 - 4071. (FMO)

3. MacNee, W.; et. al. Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax 2013, 68(8), 738 - 745. (FMO)

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