ABSTRACT
While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.
Subject(s)
Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/drug therapy , Receptors, Cytoplasmic and NuclearABSTRACT
Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound 7 is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of 7 involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of (S)-31, a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to 7. The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.
Subject(s)
Neuralgia , Quinolines , Amides/pharmacology , Amides/therapeutic use , Animals , Neuralgia/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Quinolines/pharmacology , Quinolines/therapeutic use , Structure-Activity RelationshipABSTRACT
Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure-activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of 59, a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound 59 was evaluated in mice for the inhibition of µ2 phosphorylation. Studies conducted with 59 in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain.
Subject(s)
Amides/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Brain/enzymology , Neuralgia/drug therapy , Protein Kinases/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Caco-2 Cells , Dose-Response Relationship, Drug , Drug Discovery , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Neuralgia/metabolism , Protein Kinases/chemical synthesis , Protein Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as 12 with improved potency and selectivity. Additionally 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21, which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.
ABSTRACT
The cytokine TGF-ß modulates a number of cellular activities and plays a critical role in development, hemostasis and physiology, as well as in diseases including cancer and fibrosis. TGF-ß signals through two transmembrane serine/threonine kinase receptors: TGFßR1 and TGFßR2. Multiple structures of the TGFßR1 kinase domain are known, but the structure of TGFßR2 remains unreported. Wild-type TGFßR2 kinase domain was refractory to crystallization, leading to the design of two mutated constructs: firstly, a TGFßR1 chimeric protein with seven ATP-site residues mutated to their counterparts in TGFßR2, and secondly, a reduction of surface entropy through mutation of six charged residues on the surface of the TGFßR2 kinase domain to alanines. These yielded apo and inhibitor-bound crystals that diffracted to high resolution (<2â Å). Comparison of these structures with those of TGFßR1 reveal shared ligand contacts as well as differences in the ATP-binding sites, suggesting strategies for the design of pan and selective TGFßR inhibitors.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/chemistry , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/chemistry , Adenosine Triphosphate/metabolism , Binding Sites , Crystallography, X-Ray , Humans , Ligands , Models, Molecular , Protein Binding , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type I , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/metabolismABSTRACT
Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine kinase involved in the phosphorylation of MAP proteins that regulate microtubule dynamics. Abnormal activity of MARK4 has been proposed to contribute to neurofibrillary tangle formation in Alzheimer's disease. The crystal structure of the catalytic and ubiquitin-associated domains of MARK4 with a potent pyrazolopyrimidine inhibitor has been determined to 2.8â Å resolution with an Rwork of 22.8%. The overall structure of MARK4 is similar to those of the other known MARK isoforms. The inhibitor is located in the ATP-binding site, with the pyrazolopyrimidine group interacting with the inter-lobe hinge region while the aminocyclohexane moiety interacts with the catalytic loop and the DFG motif, forcing the activation loop out of the ATP-binding pocket.
Subject(s)
Crystallization/methods , Crystallography, X-Ray/methods , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyrimidines/chemistry , Pyrimidines/metabolism , Amino Acid Sequence , Humans , Molecular Sequence Data , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolismABSTRACT
Tau-tubulin kinase 1 (TTBK1) is a dual-specificity (serine/threonine and tyrosine) kinase belonging to the casein kinase 1 superfamily. TTBK1 is a neuron-specific kinase that regulates tau phosphorylation. Hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease. Two kinase-domain constructs of TTBK1 were expressed in a baculovirus-infected insect-cell system and purified. The purified TTBK1 kinase-domain proteins were crystallized using the hanging-drop vapor-diffusion method. X-ray diffraction data were collected and the structure of TTBK1 was determined by molecular replacement both as an apo structure and in complex with a kinase inhibitor.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/chemistry , Animals , Baculoviridae/genetics , Crystallization , Crystallography, X-Ray , Electrophoresis, Polyacrylamide Gel , Humans , Magnetic Resonance Spectroscopy , Protein Conformation , Sf9 Cells , Substrate SpecificityABSTRACT
A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38ß isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.
Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Binding Sites , Crystallography, X-Ray , Humans , Hydrogen Bonding , Mitogen-Activated Protein Kinase 14/metabolism , Molecular Dynamics Simulation , Protein Binding , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of tyrosine residues, a process that involves a conserved tryptophan-proline-aspartate (WPD) loop in catalysis. In previously determined structures of PTPs, the WPD-loop has been observed in either an "open" conformation or a "closed" conformation. In the current work, X-ray structures of the catalytic domain of receptor-like protein tyrosine phosphatase γ (RPTPγ) revealed a ligand-induced "superopen" conformation not previously reported for PTPs. In the superopen conformation, the ligand acts as an apparent competitive inhibitor and binds in a small hydrophobic pocket adjacent to, but distinct from, the active site. In the open and closed WPD-loop conformations of RPTPγ, the side chain of Trp1026 partially occupies this pocket. In the superopen conformation, Trp1026 is displaced allowing a 3,4-dichlorobenzyl substituent to occupy this site. The bound ligand prevents closure of the WPD-loop over the active site and disrupts the catalytic cycle of the enzyme.
Subject(s)
Models, Molecular , Receptor-Like Protein Tyrosine Phosphatases, Class 5/antagonists & inhibitors , Thiophenes/chemistry , Amino Acid Sequence , Catalytic Domain , Crystallography, X-Ray , Humans , Hydrophobic and Hydrophilic Interactions , Ligands , Molecular Sequence Data , Protein Binding , Protein Conformation , Receptor-Like Protein Tyrosine Phosphatases, Class 5/chemistry , Structure-Activity Relationship , Thiophenes/chemical synthesisABSTRACT
Protein tyrosine phosphatase γ is a membrane-bound receptor and is designated RPTPγ. RPTPγ and two mutants, RPTPγ(V948I, S970T) and RPTPγ(C858S, S970T), were recombinantly expressed and purified for X-ray crystallographic studies. The purified enzymes were crystallized using the hanging-drop vapor-diffusion method. Crystallographic data were obtained from several different crystal forms in the absence and the presence of inhibitor. In this paper, a description is given of how three different crystal forms were obtained that were used with various ligands. An orthorhombic crystal form and a trigonal crystal form were obtained both with and without ligand, and a monoclinic crystal form was only obtained in the presence of a particularly elaborated inhibitor.
Subject(s)
Catalytic Domain , Receptor-Like Protein Tyrosine Phosphatases/chemistry , Amino Acid Sequence , Cloning, Molecular , Crystallization , Crystallography, X-Ray , Humans , Molecular Sequence Data , Receptor-Like Protein Tyrosine Phosphatases/genetics , Receptor-Like Protein Tyrosine Phosphatases/isolation & purificationABSTRACT
Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.
Subject(s)
Anti-Inflammatory Agents/chemistry , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyrroles/chemistry , Triazines/chemistry , Administration, Oral , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Arthritis/drug therapy , Binding Sites , Crystallography, X-Ray , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Mice , Mitogen-Activated Protein Kinase 14/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Rats , Structure-Activity Relationship , Triazines/pharmacology , Triazines/therapeutic useABSTRACT
The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.
Subject(s)
Mitogen-Activated Protein Kinase 14/chemistry , Protein Kinase Inhibitors/chemical synthesis , Pyrazoles/pharmacology , Animals , Crystallography, X-Ray , Mice , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Binding , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp(2) character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Pyrroles/chemical synthesis , Triazines/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Biological Availability , Caco-2 Cells , Crystallography, X-Ray , Female , Humans , Hydrogen Bonding , In Vitro Techniques , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred BALB C , Microsomes, Liver/metabolism , Mitogen-Activated Protein Kinase 14/chemistry , Models, Molecular , Molecular Conformation , Protein Binding , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Triazines/pharmacokinetics , Triazines/pharmacology , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.
Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Nitrogen/chemistry , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemistry , Sulfur/chemistry , Thiazoles/chemistry , Binding Sites , Crystallography, X-Ray , Drug Design , Mitogen-Activated Protein Kinase 14/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
Eg5 is a kinesin whose inhibition leads to cycle arrest during mitosis, making it a potential therapeutic target in cancers. Circular dichroism and isothermal titration calorimetry of our pyrrolotriazine-4-one series of inhibitors with Eg5 motor domain revealed enhanced binding in the presence of adenosine 5'-diphosphate (ADP). Using this information, we studied the interaction of this series with ADP-Eg5 complexes using a thermal shift assay. We measured up to a 7 degrees C increase in the thermal melting (T(m)) of Eg5 for an inhibitor that produced IC(50) values of 60 and 130 nM in microtubule-dependent adenosine triphosphatase (ATPase) and cell-based cytotoxicity assays, respectively. In general, the inhibitor potency of the pyrrolotriazine-4-one series in in vitro biological assays correlated with the magnitude of the thermal stability enhancement of ADP-Eg5. The thermal shift assay also confirmed direct binding of Eg5 inhibitors identified in a high-throughput screen and demonstrated that the thermal shift assay is applicable to a range of chemotypes and can be useful in evaluating both potent (nM) and relatively weakly binding (microM) leads. Overall, the thermal shift assay was found to be an excellent biophysical method for evaluating direct binding of a large number of compounds to Eg5, and it complemented the catalytic assay screens by providing an alternative determination of inhibitor potency.
Subject(s)
Biochemistry/methods , Kinesins/chemistry , Pyrroles/analysis , Pyrroles/chemistry , Triazines/analysis , Triazines/chemistry , Adenosine Diphosphate/metabolism , Biophysical Phenomena , Calorimetry , Cell Line, Tumor , Circular Dichroism , Humans , Kinesins/metabolism , Magnetic Resonance Spectroscopy , Models, Molecular , Protein Binding , Protein Denaturation , Protein Folding , Protein Structure, Tertiary , TemperatureABSTRACT
Fragment-like inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK2) include 5-hydroxyisoquinoline (IC50 approximately 85 microM). Modeling studies identified four possible binding modes for this compound. Two-dimensional (1)H-(1)H NOESY data obtained with selectively protonated samples of MK2 in complex with 5-hydroxyisoquinoline demonstrated that two of the four predicted binding modes are well populated. A second small isoquinoline was subsequently shown to bind in a single mode. NMR and modeling studies using this general approach are expected to facilitate "scaffold hopping" and structure-guided elaborations of fragment-like kinase inhibitor cores.
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Isoquinolines/pharmacology , Magnetic Resonance Spectroscopy/methods , Models, Molecular , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Binding Sites/drug effects , Crystallography, X-Ray , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Isoquinolines/chemistry , Magnetic Resonance Spectroscopy/standards , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/chemistry , Protons , Reference Standards , Structure-Activity RelationshipABSTRACT
The crystal structure of unphosphorylated p38alpha MAP kinase complexed with a representative pyrrolotriazine-based inhibitor led to the elucidation of the high-affinity binding mode of this class of compounds at the ATP-binding site. The ligand binds in an extended conformation, with one end interacting with the adenine-pocket hinge region, including a hydrogen bond from the carboxyl O atom of Met109. The other end of the ligand interacts with the hydrophobic pocket of the binding site and with the backbone N atom of Asp168 in the DFG activation loop. Addition of an extended benzylmorpholine group forces the DFG loop to flip out of position and allows the ligand to make additional interactions with the protein.
Subject(s)
Anilides/chemistry , Benzamides/chemistry , Mitogen-Activated Protein Kinase 14/chemistry , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Pyrroles/chemistry , Binding Sites , Crystallography, X-Ray , Humans , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Models, Molecular , Protein BindingABSTRACT
Mass spectrometry has gained prominence in limited proteolysis studies largely due to its unparalleled precision in determining protein molecular mass. However, proteolytic fragments usually cannot be identified through direct mass measurement, since multiple subsequences of a protein can frequently be matched to observed masses of proteolytic fragments. Therefore, additional information from N-terminal sequencing is often needed. Here we demonstrate that mass spectrometry analysis of the time course of limited proteolysis reactions provides new information that is self-sufficient to identify all proteolytic fragments. The method uses a non-specific protease like subtilisin and exploits information contained in the time-resolved dataset such as: increased likelihood of identifying larger fragments generated during initial proteolysis solely by their masses, additivity of the masses of two mutually exclusive sequence regions that generate the full-length molecule (or an already assigned subfragment), and analyses of the proteolytic subfragment patterns that are facilitated by having established the initial cleavage sites. We show that the identities of the observed proteolytic fragments can be determined by LC/MS alone because enough constraints exist in the time-resolved dataset. For a medium-sized protein, it takes about 8 h to complete the study, a significant improvement over the traditional SDS-PAGE and N-terminal sequencing method, which usually takes several days. We illustrate this method with application to the catalytic domain of mitogen-activated protein kinase-activated protein kinase-2, and compare the results with N-terminal sequencing data and the known X-ray crystal structure.
Subject(s)
Chromatography, High Pressure Liquid/methods , Mitogen-Activated Protein Kinase 1/chemistry , Peptide Hydrolases/chemistry , Sequence Analysis, Protein/methods , Spectrometry, Mass, Electrospray Ionization/methods , Amino Acid Sequence , Enzyme Activation , Molecular Sequence Data , Time FactorsABSTRACT
The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolism , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/chemistryABSTRACT
A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.