ABSTRACT
In this study we report the design, synthesis, and biological evaluation of constrained aminopyridinylimidazoles as p38α MAP kinase inhibitors. The frozen analogue approach focused on the pyridinyl unit, using purine bioisosteres as constrained structure analogues. The identification of the most potent bioisostere was followed by a further derivatization to address hydrophobic region II. In combination with C-2 modifications of the imidazole core, we were able to design highly active inhibitors on the p38α MAP kinase. The inhibitor design presented herein represents a promising and highly efficient advancement of recent stages of development in this class of p38 MAP kinase inhibitors. In combination with the highly flexible synthetic strategy, directions toward further investigations of complex C-5 modifications of diarylimidazoles are indicated.
Subject(s)
Imidazoles/chemical synthesis , Pyridines/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Drug Design , Entropy , Imidazoles/chemistry , Molecular Conformation , Molecular Docking Simulation , Purines/chemistry , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs. In this study, we report novel dibenzepinones, dibenzoxepines, and benzosuberones as p38α MAP kinase inhibitors. Previously reported dibenzepinones and dibenzoxepines were chemically modified by introduction of functional groups or removal of a phenyl ring. This should result in targeting of the hydrophobic region I, the "deep pocket", and the hinge glycine flip of the kinase. Potent inhibitors with IC(50) values in the single digit nanomolar range (up to 3 nM) were identified. Instead of targeting the "deep pocket" in the DFG-out conformation, interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography.
Subject(s)
Glycine/drug effects , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Crystallography, X-Ray , Glycine/chemistry , Magnetic Resonance Spectroscopy , Mitogen-Activated Protein Kinase 14/chemistry , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Spectrometry, Mass, Electrospray IonizationABSTRACT
Synthesis, biological testing, structure-activity relationships (SARs), and selectivity of novel disubstituted dibenzosuberone derivatives as p38 MAP kinase inhibitors are described. Hydrophilic moieties were introduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones, improving physicochemical properties as well as potency. Extremely potent inhibitors were obtained, with half-maximal inhibitory concentration (IC(50)) values in the low nM range in a whole blood assay measuring the inhibition of cytokine release. The high potency of the target compounds together with the outstanding selectivity of this novel class of compounds toward p38 mitogen activated protein (MAP) kinase as compared to other kinases indicate them to be most applicable as tools in pharmacological research and eventually they may foster a new generation of anti-inflammatory drugs.
Subject(s)
Dibenzocycloheptenes/chemical synthesis , Dibenzocycloheptenes/pharmacology , Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Chemistry Techniques, Synthetic , Dibenzocycloheptenes/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Kinetics , Models, Molecular , Protein Conformation , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Substrate Specificity , p38 Mitogen-Activated Protein Kinases/chemistryABSTRACT
Until now, a lack of inhibitors with high potency and selectivity in vivo has hampered investigation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We describe the design of skepinone-L, which is, to our knowledge, the first ATP-competitive p38 MAPK inhibitor with excellent in vivo efficacy and selectivity. Therefore, skepinone-L is a valuable probe for chemical biology research, and it may foster the development of a unique class of kinase inhibitors.
Subject(s)
Dibenzocycloheptenes/chemistry , Protein Kinase Inhibitors/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Adenosine Triphosphate , Animals , Binding, Competitive , Drug Design , Mice , Models, Molecular , Protein Interaction Domains and MotifsABSTRACT
The goal of this paper is to present and describe a novel 2D- and 3D-QSAR (quantitative structure-activity relationship) binary classification data set for the inhibition of c-Jun N-terminal kinase-3 with previously unpublished activities for a diverse set of compounds. JNK3 is an important pharmaceutical target because it is involved in many neurological disorders. Accordingly, the development of JNK3 inhibitors has gained increasing interest. 2D and 3D versions of the data set were used, consisting of 313 (70 actives) and 249 (60 actives) compounds, respectively. All compounds, for which activity was only determined for the racemate, were removed from the 3D data set. We investigated the diversity of the data sets by an agglomerative clustering with feature trees and show that the data set contains several different scaffolds. Furthermore, we show that the benchmarks can be tackled with standard supervised learning algorithms with a convincing performance. For the 2D problem, a random decision forest classifier achieves a Matthew's correlation coefficient of 0.744, the 3D problem could be modeled with a Matthew's correlation coefficient of 0.524 with 3D pharmacophores and a support vector machine. The performance of both data sets was evaluated within a nested 10-fold cross-validation. We therefore suggest that the data set is a reasonable basis for generating QSAR models for JNK3 because of its diverse composition and the performance of the classifiers presented in this study.
Subject(s)
Mitogen-Activated Protein Kinase 10/antagonists & inhibitors , Models, Molecular , HumansABSTRACT
A series of 42 naturally occurring flavonoids and one flavonoid glucuronide were tested for their ability to inhibit p38α mitogen-activated protein kinase (p38α) and c-Jun-N-terminal kinase 3 (JNK3). Potent inhibitors with IC(50) values in the low micromolar range were identified. Structure-activity relationships were evaluated and the most promising compounds were docked into the ATP binding site of these kinases. Among the different classes of flavonoids, the flavonol group showed better inhibition of p38α. Of this class, kaempferol-7,4'-dimethylether was a potent p38α inhibitor, displaying 13-fold selectivity for p38α over JNK3. The flavone compounds without a 6-methoxy group preferentially inhibited JNK3. The flavone glycoside, luteolin-7-O-glycoside, was identified as a potent inhibitor with the greatest selectivity toward JNK3. In contrast, the flavanol compounds displayed similar inhibitory activities toward both kinases.
Subject(s)
Flavonoids/chemistry , Flavonoids/pharmacology , Mitogen-Activated Protein Kinase 10/antagonists & inhibitors , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Animals , Humans , Mitogen-Activated Protein Kinase 10/chemistry , Mitogen-Activated Protein Kinase 10/metabolism , Mitogen-Activated Protein Kinase 14/chemistry , Mitogen-Activated Protein Kinase 14/metabolism , Models, Molecular , Structure-Activity RelationshipABSTRACT
The synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles as potent p38α mitogen-activated protein kinase inhibitors is described. The trisubstituted imidazole series was found to be more potent than the tetrasubstituted imidazole series. Many of these compounds show low-nanomolar activities in the isolated p38α MAP kinase inhibition assay. The structure-activity relationships between these two series are different and not comparable.
Subject(s)
Imidazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Imidazoles/chemistry , Models, Molecular , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
The p38 mitogen-activated protein (MAP) kinase alpha plays a central role in the regulation of cellular responses such as differentiation, proliferation, apoptosis, and inflammation. Inhibition of p38 results in decreased synthesis of pro-inflammatory cytokines. To date, diverse p38alpha inhibitors are in phase II clinical trials for numerous cytokine-dependent diseases. 2-Sulfanylimidazole derivatives offer advantages over the prototype inhibitor SB 203580, including fewer cytochrome P450 interactions and better kinetic properties. The aim of this study was to develop novel 1,2,4,5-tetrasubstituted pyridinylimidazoles with acyl residues at the imidazole N1 position that can interact with the kinase's hydrophobic region II (HR II) or sugar pocket (SP) to improve both selectivity and activity. The substitution pattern was optimized by variation of the acyl moiety at the N1 position of the N-aminoimidazole core. Acylation of the amino function was used for optimization and led to potent p38alpha MAPK inhibitors.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Imidazoles/chemistry , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Binding Sites , Computer Simulation , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Mitogen-Activated Protein Kinase 14/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
The p38 MAP kinase is a key enzyme in inflammatory diseases as it is involved in the biosynthesis of proinflammatory cytokines such as TNF-alpha and IL-1beta. Small molecule p38 inhibitors suppress the production of these cytokines and therefore p38 is a promising drug target for novel anti-inflammatory therapeutics. In this study, we report the design, synthesis, and SAR of novel N-substituted 11H-dibenzo[b,f]oxepin-10-ones and 5,11-dihydro-dibenzo[a,d]cyclohepten-10-ones as p38 inhibitors.
Subject(s)
Cycloheptanes/chemistry , Oxepins/chemistry , Protein Kinase Inhibitors/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Anti-Inflammatory Agents , Binding Sites , Computer Simulation , Cycloheptanes/chemical synthesis , Cycloheptanes/pharmacology , Drug Design , Interleukin-1beta/metabolism , Oxepins/chemical synthesis , Oxepins/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Various substituted 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)quinoxalines and 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)pyridopyrazines were synthesized as novel p38 alpha MAP kinase inhibitors via different short synthetic strategies with high variation possibilities. The formation of the quinoxaline/pyridopyrazine core was achieved from alpha-diketones and o-phenylenediamines/alpha-diaminopyridines under microwave irradiation. Introduction of an amino moiety at the pyridine C2 position of the 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)quinoxalines led to compounds showing potent enzyme inhibition down to the double-digit nanomolar range (6f; IC(50) = 81 nM). Replacement of the quinoxaline core with pyrido[2,3-b]pyrazine gave compound 9e with superior p38 alpha MAP kinase inhibition (IC(50) = 38 nM).
Subject(s)
Protein Kinase Inhibitors/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Quinoxalines/chemistry , Quinoxalines/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Humans , Models, Chemical , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazines/chemical synthesis , Pyridines/chemical synthesis , Quinoxalines/chemical synthesis , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
In this study, we report on the discovery of isoxazole 1 as a potent dual inhibitor of p38alpha (IC(50) = 0.45 microM) and CK1delta (IC(50) = 0.23 microM). Because only a few effective small molecule inhibitors of CK1 have been described so far, we aimed to develop this structural class toward specific agents. Molecular modeling studies comparing p38alpha/CK1delta suggested an optimization strategy leading to design, synthesis, biological characterization, and SAR of highly potent compounds including 9 (IC(50) p38alpha = 0.006 microM; IC(50) CK1delta = 1.6 microM), 13 (IC(50) p38alpha = 2.52 microM; IC(50) CK1delta = 0.033 microM), 17 (IC(50) p38alpha = 0.019 microM; IC(50) CK1delta = 0.004 microM; IC(50) CK1epsilon = 0.073 microM), and 18 (CKP138) (IC(50) p38alpha = 0.041 microM; IC(50) CK1delta = 0.005 microM; IC(50) CK1epsilon = 0.447 microM) possessing differentiated specificity. Selected compounds were profiled over 76 kinases and evaluation of their cellular efficacy showed 18 (CKP138) to be a highly potent and dual-specific inhibitor of CK1delta and p38alpha.
Subject(s)
Casein Kinase Idelta/antagonists & inhibitors , Imidazoles/chemistry , Imidazoles/pharmacology , Isoxazoles/chemistry , Isoxazoles/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Amino Acid Sequence , Animals , Binding, Competitive , Casein Kinase Idelta/chemistry , Casein Kinase Idelta/genetics , Casein Kinase Idelta/metabolism , Cell Line , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , Imidazoles/metabolism , Inhibitory Concentration 50 , Isoxazoles/metabolism , Mitogen-Activated Protein Kinase 14/chemistry , Mitogen-Activated Protein Kinase 14/metabolism , Models, Molecular , Molecular Sequence Data , Mutation , Protein Conformation , Rats , Trophoblasts/cytology , Trophoblasts/drug effectsABSTRACT
In the framework of investigating the role of heteroatoms in pyridinyl-substituted 5-membered (hetero)cycles as potential p38alpha MAP kinase inhibitor scaffolds, cyclopentene, pyrrole, furan, and imidazole analogues were synthesized and tested with respect to their ability to inhibit p38alpha MAP kinase. The vicinal pyridine/4-fluorophenyl pharmacophore was conserved, such as in the prototypical imidazole inhibitor SB203580. The strength of the HB interaction was calculated and compared to the biological data.
Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Pyridines/chemical synthesis , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Furans/chemical synthesis , Furans/chemistry , Hydrogen Bonding , Imidazoles/chemical synthesis , Imidazoles/chemistry , Mitogen-Activated Protein Kinase 14/chemistry , Pyridines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship , ThermodynamicsABSTRACT
In this study we report on the specificity profiling of the MAP kinase inhibitors 1, 2, and 3 in a panel of 78 protein kinases including the MAPK isoforms p38(alpha,beta,gamma,delta), JNK1/2/3, and ERK1/2/8 showing 3-(4-fluorophenyl)-4-pyridin-4-ylquinolin-2(1H)-one (1) to be highly selective for p38alphaMAPK with an IC(50) of 1.8 microM. In contrast, besides p38alpha the isoxazoles 2 and 3 significantly inhibited JNK2/3 and further kinases beyond the MAPK family such as PKA, PKD, Lck, and CK1. By using sequence alignment and homology models of different members of the MAPK family the binding mode determining selectivity of 1 for the p38alpha isoform was investigated. For lead optimization of 1 a straightforward tandem-Buchwald-aldol synthetic approach toward the flexible decoration of the quinolin-2(1H)-one scaffold was employed. SAR for derivatives of 1 at the isolated p38alphaMAPK are presented.