Friday, January 20, 2017

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].

PH-797804 racemic and atropisomers with activity
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
Ki (P38α binding assay) = 5.8 ± 0.3, 3.9, 183 nM


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
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
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