Design, synthesis and activity of a potent, selective series of N -aryl pyridinone inhibitors of p38 kinase (original) (raw)
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Structural basis for p38α MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity
Nature Structural Biology, 2003
Mitogen-activated protein kinases (MAPKs) are constituents of numerous signal transduction pathways that control complex processes such as differentiation, proliferation and cell death. They are also involved in signaling pathways that respond rapidly to environmental changes, such as those required for homeostasis and acute hormonal responses 1-4 . Members of the MAP kinase family share sequence similarity and conserved structural motifs, and are all activated by dual phosphorylation of conserved threonine and tyrosine residues in the activation loop. However, the various MAP kinases are responsive to different extracellular stimuli, and each activates a unique, although overlapping, spectrum of cellular targets. Whereas the extracellular signal-regulated kinases (ERKs) are activated in response to hormones and growth factors, the c-Jun N-terminal kinases (JNKs) and p38α are activated by lipopolysaccharide (LPS) and by environmental stresses such as heat shock, hyperosmolarity and radiation 5-9 .
Journal of Medicinal Chemistry, 2007
The main recognition characteristics of the ATP binding site of p38 mitogen activated protein kinase alpha (p38R MAPK) have been explored by a combination of modeling and bioinformatics techniques, making special emphasis in the characteristics of the site that justifies binding specificity with respect to other MAP kinases. Particularly, we have analyzed the binding mode of a new family of p38 MAPK inhibitors based on the pyridinyl-heterocycle core. This family of compounds has a marked pseudosymmetry and can exist in different tautomeric forms, which makes the determination of the binding mode especially challenging. A combination of homology modeling, quantum mechanics, classical docking, and molecular dynamics calculations allowed us to determine the main characteristics defining the binding mode of this new scaffold in the ATP binding site of p38R. A set of free energy calculations allowed us to verify the binding mode proposed, giving an overall excellent agreement with the experimental values. Finally, the binding mode of this new family of compounds was compared to that of other members of the pyridinyl and pyrimidinyl heterocycle class. (results of quantum mechanical calculations on the different tautomeric species) and graph S1 (theoretical vs experimental relative free energies of binding for compound 13 and derivatives). This material is available free of charge via the Internet at http://pubs.acs.org.
Journal of Medicinal Chemistry, 2003
We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38R MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38R inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important π-CH 2 interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38R by 16-17°C translating into K d values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-R production when dosed orally in mice.
p38 MAP kinase inhibitors. Part 6: 2-Arylpyridazin-3-ones as templates for inhibitor design
Bioorganic & Medicinal Chemistry Letters, 2006
p38 inhibitors based on 3,4-dihydropyrido [4,3-d]pyrimidazin-2-one template were synthesized and their SAR explored. Benchmark compounds 30, 35, and 36 were found to be potent against the enzyme. Crystal structure of p38 in complex with 30 indicated a key p-stacking interaction with the pendant tyrosine residue-35 in the glycine-rich loop.
Molecular Basis for p38 Protein Kinase Inhibitor Specificity
Biochemistry, 1999
p38 is a member of the mitogen-activated protein (MAP) kinase family and is a critical enzyme in the proinflammatory cytokine pathway. Other MAP kinase group members that share both structural and functional homology to p38 include the c-Jun NH 2 -terminal kinases (JNKs or SAPKs) and the extracellular-regulated protein kinases (ERKs). In this study, we determined the molecular basis for p38R inhibitor specificity exhibited by five compounds in the diarylimidazole, triarylimidazole, and triarylpyrrole classes of protein kinase inhibitors. These compounds are significantly more potent inhibitors of p38 compared to the JNKs and ERKs. Three active site ATP-binding domain residues in p38, T106, M109, and A157, selected based on primary sequence alignment, molecular modeling, and X-ray crystal structure data, were mutated to assess their role in inhibitor binding and enzymatic catalysis. All mutants, with the exception of T106M, had kinase activity within 3-fold of wild-type p38. Mutation of T106 to glutamine, the residue present at the corresponding position in ERK-2, or methionine, the corresponding residue in p38γ, p38δ, and the JNKs, rendered all five inhibitors ineffective. The diarylimidazoles had approximately a 6-fold decrease in potency toward M109A p38. For the mutant A157V, all diarylimidazoles and triarylimidazoles tested were 5-10-fold more potent compared with wild-type p38. In contrast, two triarylpyrroles were 15-40-fold less potent versus A157V p38. These results showed that the molecular basis for the specificity of the p38 inhibitors was attributed largely to threonine 106 in p38 and that methionine 109 contributes to increased binding affinity for imidazole based inhibitors.
Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase
Bioorganic & medicinal …, 2009
The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38a. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.
Journal of Medicinal Chemistry, 2010
The p38R mitogen-activated protein (MAP) kinase is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1β and tumor necrosis factor R. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease, as well as other diseases where aberrant cytokine signaling is the driver of disease. In this communication, we describe a novel class of 7-alkyl-1,5-bis-aryl-pyrazolopyridinone-based p38R inhibitors. In particular, compound 3f is highly potent in the enzyme and cell-based assays, selective in an Ambit kinase screen, and efficacious (ED 50 e 0.01 mg/kg) in the rat collagen induced arthritis (CIA) model. a Abbreviations: AUC, area under the curve; CIA, collagen-induced arthritis; COPD, chronic obstructive pulmonary disease; DFG, Asp-Phe-Gly sequence in ATP binding site; hPXR, human pregnane X receptor; hWB, human whole blood; IL, Interleukin; RA, rheumatoid arthritis; MFI, mean fluorescence intensity; THP1, human acute monocytic leukemia cell line; MAP, mitogen-activated protein; MK2, MAP-KAP kinase 2; TNFR, Tumor necrosis factor alpha; hERG, human Ether-a-go-go Related Gene; SAR, structure-activity relationship.
Continued exploration of the triazolopyridine scaffold as a platform for p38 MAP kinase inhibition
Bioorganic & Medicinal Chemistry Letters, 2010
The structure based drug design, synthesis and structure-activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.