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1.
Brain ; 144(10): 3226-3238, 2021 11 29.
Article in English | MEDLINE | ID: mdl-33964142

ABSTRACT

Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by sterile alpha and TIR motif containing 1 (SARM1) is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved programme of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders. Using a biochemical assay for SARM1 NADase we identified a novel series of potent and selective irreversible isothiazole inhibitors of SARM1 enzymatic activity that protected rodent and human axons in vitro. In sciatic nerve axotomy, we observed that these irreversible SARM1 inhibitors decreased a rise in nerve cADPR and plasma neurofilament light chain released from injured sciatic nerves in vivo. In a mouse paclitaxel model of CIPN we determined that Sarm1 knockout mice prevented loss of axonal function, assessed by sensory nerve action potential amplitudes of the tail nerve, in a gene-dosage-dependent manner. In that CIPN model, the irreversible SARM1 inhibitors prevented loss of intraepidermal nerve fibres induced by paclitaxel and provided partial protection of axonal function assessed by sensory nerve action potential amplitude and mechanical allodynia.


Subject(s)
Armadillo Domain Proteins/antagonists & inhibitors , Axons/drug effects , Cytoskeletal Proteins/antagonists & inhibitors , Paclitaxel/toxicity , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/drug therapy , Thiazoles/therapeutic use , Animals , Antineoplastic Agents, Phytogenic/toxicity , Armadillo Domain Proteins/deficiency , Armadillo Domain Proteins/genetics , Axons/metabolism , Cells, Cultured , Cytoskeletal Proteins/deficiency , Cytoskeletal Proteins/genetics , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Induced Pluripotent Stem Cells/drug effects , Induced Pluripotent Stem Cells/metabolism , Mice , Mice, Knockout , Peripheral Nervous System Diseases/genetics , Peripheral Nervous System Diseases/metabolism , Thiazoles/pharmacology
2.
Cell Rep ; 34(1): 108588, 2021 01 05.
Article in English | MEDLINE | ID: mdl-33406435

ABSTRACT

Axonal degeneration is responsible for disease progression and accumulation of disability in many neurodegenerative conditions. The axonal degenerative process can generate a metastable pool of damaged axons that remain structurally and functionally viable but fated to degenerate in the absence of external intervention. SARM1, an NADase that depletes axonal energy stores upon activation, is the central driver of an evolutionarily conserved program of axonal degeneration. We identify a potent and selective small molecule isoquinoline inhibitor of SARM1 NADase that recapitulates the SARM1-/- phenotype and protects axons from degeneration induced by axotomy or mitochondrial dysfunction. SARM1 inhibition post-mitochondrial injury with rotenone allows recovery and rescues axons that already entered the metastable state. We conclude that SARM1 inhibition with small molecules has the potential to treat axonopathies of the central and peripheral nervous systems by preventing axonal degeneration and by allowing functional recovery of a metastable pool of damaged, but viable, axons.


Subject(s)
Armadillo Domain Proteins/drug effects , Armadillo Domain Proteins/physiology , Axons/physiology , Cytoskeletal Proteins/drug effects , Cytoskeletal Proteins/physiology , Isoquinolines/pharmacology , Animals , Biomarkers/metabolism , Cell Line , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , NAD+ Nucleosidase/drug effects , NAD+ Nucleosidase/physiology , Nerve Degeneration/drug therapy , Neurodegenerative Diseases/drug therapy , Phenotype , Recovery of Function
3.
Trends Pharmacol Sci ; 41(4): 281-293, 2020 04.
Article in English | MEDLINE | ID: mdl-32107050

ABSTRACT

Attempts to develop neuroprotective treatments for neurodegenerative disorders have not yet been clinically successful. Axonal degeneration has been recognized as a predominant driver of disability and disease progression in central nervous system (CNS) diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Parkinson's disease, peripheral nervous system (PNS) disorders such as chemotherapy-induced, diabetic, and inherited neuropathies, and ocular disorders, such as glaucoma. In recent years, sterile alpha and TIR motif containing 1 (SARM1) has emerged as the first compelling axonal-specific target for therapeutic intervention. In this review, we discuss the role of axonal degeneration in neurodegenerative disorders, with a focus on SARM1 and the discovery of its intrinsic enzymatic function. Establishment of neurofilament light chain (NfL) as a reliable biomarker of axonal damage, and the availability of an ultrasensitive method for measuring NfL in plasma or serum, provide translational tools to make development of axonal protective, SARM1 inhibitors a viable approach to treat multiple neurodegenerative disorders.


Subject(s)
Armadillo Domain Proteins/antagonists & inhibitors , Axons/pathology , Cytoskeletal Proteins/antagonists & inhibitors , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/pathology , Animals , Armadillo Domain Proteins/metabolism , Axons/drug effects , Axons/enzymology , Cytoskeletal Proteins/metabolism , Humans , Molecular Targeted Therapy , Neurodegenerative Diseases/enzymology
4.
Exp Neurol ; 329: 113252, 2020 07.
Article in English | MEDLINE | ID: mdl-32087251

ABSTRACT

SARM1 is the central executioner of pathological axon degeneration, promoting axonal demise in response to axotomy, traumatic brain injury, and neurotoxic chemotherapeutics that induce peripheral neuropathy. SARM1 is an injury-activated NAD+ cleavage enzyme, and this NADase activity is required for the pro-degenerative function of SARM1. At present, SARM1 function is assayed by either analysis of axonal loss, which is far downstream of SARM1 enzymatic activity, or via NAD+ levels, which are regulated by many competing pathways. Here we explored the utility of measuring cADPR, a product of SARM1-dependent cleavage of NAD+, as an in cell and in vivo biomarker of SARM1 enzymatic activity. We find that SARM1 is a major producer of cADPR in cultured dorsal root ganglion (DRG) neurons, sciatic nerve, and brain, demonstrating that SARM1 has basal activity in the absence of injury. Following injury, there is a dramatic SARM1-dependent increase in the levels of axonal cADPR that precedes morphological axon degeneration. In vivo, there is also a rapid and large injury-stimulated increase in cADPR in sciatic and optic nerves. The increase in cADPR after injury is proportional to SARM1 gene dosage, suggesting that SARM1 activity is the prime regulator of cADPR levels. The role of cADPR as an important calcium mobilizing agent prompted exploration of its functional contribution to axon degeneration. We used multiple bacterial and mammalian engineered enzymes to manipulate cADPR levels in neurons but found no changes in the time course of axonal degeneration, suggesting that cADPR is unlikely to be an important contributor to the degenerative mechanism. Using cADPR as a SARM1 biomarker, we find that SARM1 can be partially activated by a diverse array of mitochondrial toxins administered at doses that do not induce axon degeneration. Hence, the subcritical activation of SARM1 induced by mitochondrial dysfunction may contribute to the axonal vulnerability common to many neurodegenerative diseases. Finally, we assay levels of both nerve cADPR and plasma neurofilament light chain (NfL) following nerve injury in vivo, and demonstrate that both biomarkers are excellent readouts of SARM1 activity, with cADPR reporting the early molecular changes in the nerve and NfL reporting subsequent axonal breakdown. The identification and characterization of cADPR as a SARM1 biomarker will help identify neurodegenerative diseases in which SARM1 contributes to axonal loss and expedite target validation studies of SARM1-directed therapeutics.


Subject(s)
Armadillo Domain Proteins/metabolism , Axons/metabolism , Cyclic ADP-Ribose/metabolism , Cytoskeletal Proteins/metabolism , Gene Dosage/physiology , Nerve Degeneration/metabolism , Animals , Armadillo Domain Proteins/genetics , Axons/pathology , Biomarkers/metabolism , Brain/metabolism , Brain/pathology , Cells, Cultured , Cyclic ADP-Ribose/genetics , Cytoskeletal Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Nerve Degeneration/genetics , Nerve Degeneration/pathology , Sciatic Nerve/metabolism , Sciatic Nerve/pathology
5.
ChemMedChem ; 7(2): 273-80, 2012 Feb 06.
Article in English | MEDLINE | ID: mdl-22174080

ABSTRACT

PH-797804 ((aS)-3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl}-N,4-dimethylbenzamde) is a diarylpyridinone inhibitor of p38 mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), 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 predicts a remarkably high rotational energy barrier of >30 kcal mol(-1), corresponding to a half-life of more than one hundred years at room temperature. This gives rise to discrete conformational spaces for the N-phenylpyridinone group, and as a result, two atropic isomers that do not interconvert under ambient conditions. Molecular modeling studies predict that the two isomers should differ in their binding affinity for p38α kinase; whereas the atropic S (aS) isomer binds favorably, the opposite aR isomer incurs significant steric interference with p38α kinase. The two isomers were subsequently identified and separated by chiral chromatography. IC50 values from p38α kinase assays confirm that one atropisomer is >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. Extensive pharmacological characterization supports that PH-797804 carries most activity both in vitro and in vivo, and it has a stability profile compatible with oral formulation and delivery options.


Subject(s)
Benzamides/chemistry , Protein Kinase Inhibitors/chemistry , Pyridones/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Arthritis/drug therapy , Benzamides/pharmacology , Benzamides/therapeutic use , Computer Simulation , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Female , Lipopolysaccharides/toxicity , Male , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Pyridones/pharmacology , Pyridones/therapeutic use , Quantum Theory , Rats , Receptors, Cell Surface , p38 Mitogen-Activated Protein Kinases/metabolism
6.
Bioorg Med Chem Lett ; 21(13): 4059-65, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21640588

ABSTRACT

A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation.


Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyridones/chemical synthesis , Pyridones/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Disease Models, Animal , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Male , Microsomes, Liver/enzymology , Molecular Structure , Pyridazines/chemistry , Pyridazines/pharmacology , Pyridones/chemistry , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley
7.
Bioorg Med Chem Lett ; 21(13): 4066-71, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21641211

ABSTRACT

The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (-)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (-)-4a are described.


Subject(s)
Benzamides/chemical synthesis , Benzamides/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrones/chemical synthesis , Pyrones/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Benzamides/chemistry , Disease Models, Animal , Dogs , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Macaca fascicularis , Male , Molecular Structure , Pyridones , Pyrones/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/chemistry , p38 Mitogen-Activated Protein Kinases/pharmacology
8.
Bioorg Med Chem Lett ; 21(13): 3856-60, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21620699

ABSTRACT

A novel series of highly potent and selective p38 MAP kinase inhibitors was developed originating from a substituted N-aryl-6-pyrimidinone scaffold. SAR studies coupled with in vivo evaluations in rat arthritis model culminated in the identification of 10 with excellent oral efficacy. Compound 10 exhibited a significantly enhanced dissolution rate compared to 1, translating to a high oral bioavailability (>90%) in rat. In animal studies 10 inhibited LPS-stimulated production of tumor necrosis factor-α in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model.


Subject(s)
Protein Kinase Inhibitors/therapeutic use , Pyrimidinones/therapeutic use , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Administration, Oral , Animals , Arthritis/drug therapy , Arthritis, Experimental , Caco-2 Cells , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Male , Models, Molecular , Protein Kinase Inhibitors/chemistry , Pyrimidinones/chemistry , Rats , Rats, Inbred Lew , Structure-Activity Relationship
9.
10.
Bioorg Med Chem Lett ; 21(6): 1827-31, 2011 Mar 15.
Article in English | MEDLINE | ID: mdl-21316220

ABSTRACT

This report describes the design and synthesis of a series of CCR2 antagonists incorporating novel non-aryl/heteroaryl RHS (right hand side) motifs. Previous SAR in the area has suggested an aryl/heteroaryl substituent as a necessary structural feature for binding to the CCR2 receptor. Herein we describe the SAR with regards to potency (binding to hCCR2), dofetilide activity and metabolic stability (in vitro HLM) for this series. The resulting outcome was the identification of compounds with excellent properties for the investigation of the role of CCR2 in disease.


Subject(s)
Drug Design , Receptors, CCR2/antagonists & inhibitors , Binding Sites , Models, Molecular , Structure-Activity Relationship
11.
Bioorg Med Chem Lett ; 21(9): 2626-30, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21315584

ABSTRACT

We describe the systematic optimization, focused on the improvement of CV-TI, of a series of CCR2 antagonists. This work resulted in the identification of 10 (((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone) which possessed a low projected human dose 35-45mg BID and a CV-TI=3800-fold.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Receptors, CCR2/agonists , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Biological Assay , Humans , Inhibitory Concentration 50 , Microsomes/drug effects , Microsomes/metabolism , Molecular Structure , Piperazines/pharmacokinetics , Protein Binding/drug effects , Pyridazines/pharmacokinetics , Receptors, CCR2/blood , Structure-Activity Relationship
12.
ACS Med Chem Lett ; 2(12): 913-8, 2011 Dec 08.
Article in English | MEDLINE | ID: mdl-24900280

ABSTRACT

We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in vivo ADMET profile. INCB8761/PF-4136309 has entered human clinical trials.

13.
Toxicol Pathol ; 38(4): 606-18, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20448081

ABSTRACT

Exposure to moderately selective p38alpha mitogen-activated protein kinase (MAPK) inhibitors in the Beagle dog results in an acute toxicity consisting of mild clinical signs (decreased activity, diarrhea, and fever), lymphoid necrosis and depletion in the gut-associated lymphoid tissue (GALT), mesenteric lymph nodes and spleen, and linear colonic and cecal mucosal hemorrhages. Lymphocyte apoptosis and necrosis in the GALT is the earliest and most prominent histopathologic change observed, followed temporally by neutrophilic infiltration and acute inflammation of the lymph nodes and spleen and multifocal mucosal epithelial necrosis and linear hemorrhages in the colon and cecum. These effects are not observed in the mouse, rat, or cynomolgus monkey. To further characterize the acute toxicity in the dog, a series of in vivo, in vitro, and immunohistochemical studies were conducted to determine the relationship between the lymphoid and gastrointestinal (GI) toxicity and p38 MAPK inhibition. Results of these studies demonstrate a direct correlation between p38alpha MAPK inhibition and the acute lymphoid and gastrointestinal toxicity in the dog. Similar effects were observed following exposure to inhibitors of MAPK-activated protein kinase-2 (MK2), further implicating the role of p38alpha MAPK signaling pathway inhibition in these effects. Based on these findings, the authors conclude that p38alpha MAPK inhibition results in acute lymphoid and GI toxicity in the dog and is unique among the species evaluated in these studies.


Subject(s)
Gastrointestinal Diseases/chemically induced , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Lymphatic Diseases/chemically induced , Protein Kinase Inhibitors/toxicity , Protein Serine-Threonine Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , B-Lymphocytes/metabolism , Blotting, Western , Cell Proliferation/drug effects , Cells, Cultured , Colon/drug effects , Colon/pathology , Dogs , Female , Gastrointestinal Diseases/pathology , Gastrointestinal Hemorrhage/chemically induced , Humans , Immunohistochemistry , Intracellular Signaling Peptides and Proteins/metabolism , Linear Models , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymphatic Diseases/pathology , Macaca fascicularis , Male , Mice , Protein Serine-Threonine Kinases/metabolism , Rats , Rats, Sprague-Dawley , Spleen/cytology , Spleen/metabolism , T-Lymphocytes/metabolism , Toxicity Tests, Acute , p38 Mitogen-Activated Protein Kinases/metabolism
14.
Bioorg Med Chem Lett ; 20(10): 3146-9, 2010 May 15.
Article in English | MEDLINE | ID: mdl-20395140

ABSTRACT

The synthesis, structure-activity relationship and modeling of a series of 5-substituted-N-aryl pyridazinone based p38alpha inhibitors are described. In comparing the series to the similar N-aryl pyridinone series, it was found that the pyridazinones maintained a weaker interaction to the p38 enzyme, and therefore showed generally weaker binding than the pyridinones.


Subject(s)
Anti-Infective Agents/chemistry , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyridazines/chemistry , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Binding Sites , Computer Simulation , Drug Discovery , Mitogen-Activated Protein Kinase 14/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 20(8): 2634-8, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20227876

ABSTRACT

Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38alpha kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.


Subject(s)
Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Catalytic Domain , Humans , Models, Molecular , p38 Mitogen-Activated Protein Kinases/metabolism
16.
J Pharmacol Exp Ther ; 331(3): 882-95, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19720877

ABSTRACT

Signal transduction through the p38 mitogen-activated protein (MAP) kinase pathway is central to the transcriptional and translational control of cytokine and inflammatory mediator production. p38 MAP kinase inhibition hence constitutes a promising therapeutic strategy for treatment of chronic inflammatory diseases, based upon its potential to inhibit key pathways driving the inflammatory and destructive processes in these debilitating diseases. The present study describes the pharmacological properties of the N-phenyl pyridinone p38 MAP kinase inhibitor benzamide [3- [3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2- oxo-1(2H)-pyridinyl]-N,4-dimethyl-, (-)-(9CI); PH-797804]. PH-797804 is an ATP-competitive, readily reversible inhibitor of the alpha isoform of human p38 MAP kinase, exhibiting a K(i) = 5.8 nM. In human monocyte and synovial fibroblast cell systems, PH-797804 blocks inflammation-induced production of cytokines and proinflammatory mediators, such as prostaglandin E(2), at concentrations that parallel inhibition of cell-associated p38 MAP kinase. After oral dosing, PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. Furthermore, PH-797804 demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis. Finally, PH-797804 reduced tumor necrosis factor-alpha and interleukin-6 production in clinical studies after endotoxin administration in a dose-dependent manner, paralleling inhibition of the target enzyme. Low-nanomolar biochemical enzyme inhibition potency correlated with p38 MAP kinase inhibition in human cells and in vivo studies. In addition, a direct correspondence between p38 MAP kinase inhibition and anti-inflammatory activity was observed with PH-797804, thus providing confidence in dose projections for further human studies in chronic inflammatory disease.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamides/therapeutic use , Pyrones/therapeutic use , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Adolescent , Adult , Animals , Anti-Inflammatory Agents, Non-Steroidal/blood , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Experimental/enzymology , Arthritis, Experimental/immunology , Arthritis, Experimental/metabolism , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/enzymology , Arthritis, Rheumatoid/immunology , Benzamides/blood , Benzamides/chemistry , Benzamides/pharmacology , Bone Density/drug effects , Bone Marrow Cells/drug effects , Bone Marrow Cells/enzymology , Bone Marrow Cells/immunology , Cell Line , Cytokines/biosynthesis , Cytokines/blood , Dinoprostone/biosynthesis , Drug Evaluation, Preclinical , Female , Humans , Lipopolysaccharides/pharmacology , Macaca fascicularis , Male , Mice , Mice, Inbred DBA , Middle Aged , Monocytes/drug effects , Monocytes/enzymology , Monocytes/immunology , Osteoclasts/drug effects , Osteoclasts/enzymology , Osteoclasts/immunology , Pyridones , Pyrones/blood , Pyrones/chemistry , Pyrones/pharmacology , Rats , Rats, Inbred Lew , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/enzymology , Systemic Inflammatory Response Syndrome/immunology , Young Adult
17.
Bioorg Med Chem Lett ; 19(20): 5851-6, 2009 Oct 15.
Article in English | MEDLINE | ID: mdl-19751974

ABSTRACT

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 p38alpha. 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.


Subject(s)
Anti-Inflammatory Agents/chemistry , Protein Kinase Inhibitors/chemistry , Pyridones/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Drug Discovery , Humans , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , JNK Mitogen-Activated Protein Kinases/metabolism , Male , Microsomes, Liver/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyridones/chemical synthesis , Pyridones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/metabolism
18.
Biochemistry ; 48(27): 6402-11, 2009 Jul 14.
Article in English | MEDLINE | ID: mdl-19496616

ABSTRACT

PH-797804 is a diarylpyridinone inhibitor of p38alpha mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed by experiments. On the basis of structural comparison with a different biaryl pyrazole template and supported by dozens of high-resolution crystal structures of p38alpha inhibitor complexes, PH-797804 is predicted to possess a high level of specificity across the broad human kinase genome. We used a structural bioinformatics approach to identify two selectivity elements encoded by the TXXXG sequence motif on the p38alpha kinase hinge: (i) Thr106 that serves as the gatekeeper to the buried hydrophobic pocket occupied by 2,4-difluorophenyl of PH-797804 and (ii) the bidentate hydrogen bonds formed by the pyridinone moiety with the kinase hinge requiring an induced 180 degrees rotation of the Met109-Gly110 peptide bond. The peptide flip occurs in p38alpha kinase due to the critical glycine residue marked by its conformational flexibility. Kinome-wide sequence mining revealed rare presentation of the selectivity motif. Corroboratively, PH-797804 exhibited exceptionally high specificity against MAP kinases and the related kinases. No cross-reactivity was observed in large panels of kinase screens (selectivity ratio of >500-fold). In cellular assays, PH-797804 demonstrated superior potency and selectivity consistent with the biochemical measurements. PH-797804 has met safety criteria in human phase I studies and is under clinical development for several inflammatory conditions. Understanding the rationale for selectivity at the molecular level helps elucidate the biological function and design of specific p38alpha kinase inhibitors.


Subject(s)
Benzamides/pharmacology , Computational Biology , Protein Kinase Inhibitors/pharmacology , Pyrones/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Benzamides/chemistry , Crystallography, X-Ray , Humans , Hydrogen Bonding , Models, Molecular , Molecular Structure , Phosphorylation , Protein Kinase Inhibitors/chemistry , Pyridones , Pyrones/chemistry , Substrate Specificity , p38 Mitogen-Activated Protein Kinases/metabolism
19.
Bioorg Med Chem Lett ; 18(17): 4872-5, 2008 Sep 01.
Article in English | MEDLINE | ID: mdl-18691886

ABSTRACT

Relationships between physicochemical drug properties and toxicity were inferred from a data set consisting of animal in vivo toleration (IVT) studies on 245 preclinical Pfizer compounds; an increased likelihood of toxic events was found for less polar, more lipophilic compounds. This trend held across a wide range of types of toxicity and across a broad swath of chemical space.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , Pharmaceutical Preparations/chemistry , Structure-Activity Relationship , Animals , Dogs , Drug Evaluation, Preclinical , Female , Humans , Male , Rats
20.
J Med Chem ; 50(23): 5712-9, 2007 Nov 15.
Article in English | MEDLINE | ID: mdl-17948975

ABSTRACT

A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease.


Subject(s)
Antirheumatic Agents/chemical synthesis , Piperazines/chemical synthesis , Pyrazoles/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Antirheumatic Agents/chemistry , Antirheumatic Agents/pharmacology , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Collagen , Crystallography, X-Ray , Male , Mice , Mice, Inbred DBA , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rats , Rats, Inbred Lew , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/chemistry
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