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1.
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
2.
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
3.
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
4.
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
5.
Bioorg Med Chem Lett ; 19(19): 5708-11, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19713109
6.
Pharmacology ; 84(1): 42-60, 2009.
Article in English | MEDLINE | ID: mdl-19590255

ABSTRACT

SD0006 is a diarylpyrazole that was prepared as an inhibitor of p38 kinase-alpha (p38alpha). In vitro, SD0006 was selective for p38alpha kinase over 50 other kinases screened (including p38gamma and p38delta with modest selectivity over p38beta). Crystal structures with p38alpha show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38alpha that can confer advantages over other ATP competitive inhibitors. Direct correlation between inhibition of p38alpha activity and that of lipopolysaccharide-stimulated TNFalpha release was established in cellular models and in vivo, including a phase 1 clinical trial. Potency (IC(50)) for inhibiting tumor necrosis factor-alpha (TNFalpha) release, in vitro and in vivo, was <200 nmol/l. In vivo, SD0006 was effective in the rat streptococcal-cell-wall-induced arthritis model, with dramatic protective effects on paw joint integrity and bone density as shown by radiographic analysis. In the murine collagen-induced arthritis model, equivalence was demonstrated to anti-TNFalpha treatment. SD0006 also demonstrated good oral anti-inflammatory efficacy with excellent cross-species correlation between the rat, cynomolgus monkey, and human. SD0006 suppressed expression of multiple proinflammatory proteins at both the transcriptional and translational levels. These properties suggest SD0006 could provide broader therapeutic efficacy than cytokine-targeted monotherapeutics.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Experimental/drug therapy , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Administration, Oral , Animals , Bone Density/drug effects , Cell Line , Endotoxemia/drug therapy , Endotoxemia/metabolism , Female , Humans , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/physiopathology , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Lipopolysaccharides/pharmacology , Macaca fascicularis , Male , Mice , Mice, Inbred DBA , Models, Molecular , Pain/drug therapy , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
7.
Arthritis Rheum ; 56(1): 117-28, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17195214

ABSTRACT

OBJECTIVE: The NF-kappaB signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF-kappaB activity is regulated by the IKK-2 kinase during inflammatory responses. To elucidate how IKK-2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibody-induced arthritis. METHODS: ML120B, a potent, small molecule inhibitor of IKK-2, was administered to arthritic animals, and disease activity was monitored. NF-kappaB activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase-polymerase chain reaction was used to evaluate gene expression in joints. Protease-activated near-infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints. RESULTS: Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF-kappaB activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF-kappaB pathway, i.e., KC, epithelial neutrophil-activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor alpha, interleukin-1beta, interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints. CONCLUSION: Our data demonstrate that IKK-2 inhibition in the murine model of antibody-induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.


Subject(s)
Antirheumatic Agents/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Carbolines/pharmacology , Enzyme Inhibitors/pharmacology , I-kappa B Kinase/antagonists & inhibitors , Niacinamide/analogs & derivatives , Spectroscopy, Near-Infrared/methods , Administration, Oral , Animals , Arthritis, Experimental/enzymology , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/enzymology , Arthritis, Rheumatoid/pathology , Dose-Response Relationship, Drug , Female , Gene Expression/drug effects , I-kappa B Kinase/metabolism , Joints/drug effects , Joints/metabolism , Joints/pathology , Mice , Mice, Inbred BALB C , NF-kappa B/genetics , NF-kappa B/metabolism , Niacinamide/pharmacology , RNA, Messenger/metabolism , Spectrometry, Fluorescence/methods , Up-Regulation/drug effects
8.
Arthritis Rheum ; 54(10): 3163-73, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17009244

ABSTRACT

OBJECTIVE: The IKK complex regulates NF-kappaB activation, an important pathway implicated in the rheumatoid arthritis (RA) disease process. This study was undertaken to assess the efficacy of N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a potent and selective small molecule inhibitor of IKKbeta. METHODS: Polyarthritis was induced in rats by injection of Freund's complete adjuvant into the hind footpad. ML120B was administered orally twice daily, either prophylactically or therapeutically. Paw volumes and body weights were measured every 2-3 days throughout the study. We assessed bone erosions by several methods: histologic evaluation, quantitative micro-computed tomography (micro-CT) imaging analysis, and measurement of type I collagen fragments in the serum. Quantitative polymerase chain reaction was used to evaluate expression of messenger RNA for genes related to inflammation and to bone and cartilage integrity. RESULTS: Oral administration of ML120B inhibited paw swelling in a dose-dependent manner (median effective dosage 12 mg/kg twice daily) and offered significant protection against arthritis-induced weight loss as well as cartilage and bone erosion. We were able to directly demonstrate that NF-kappaB activity in arthritic joints was reduced after ML120B administration. Also, we observed that down-regulation of the NF-kappaB pathway via IKKbeta inhibition dampened the chronic inflammatory process associated with rat adjuvant-induced arthritis. CONCLUSION: The results of the present study suggest that IKKbeta inhibition is an effective therapeutic approach to treat both the inflammation and the bone/cartilage destruction observed in RA. Methods for the determination of serum markers for bone and cartilage destruction, as well as micro-CT analysis, may aid in predicting and evaluating the therapeutic efficacy of IKKbeta inhibition therapy in humans.


Subject(s)
Arthritis, Rheumatoid/physiopathology , Bone and Bones/pathology , Cartilage/pathology , I-kappa B Kinase/antagonists & inhibitors , Animals , Arthritis, Experimental , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/metabolism , Bone and Bones/metabolism , Carbolines/pharmacology , Cartilage/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Freund's Adjuvant , Gene Expression Regulation , I-kappa B Kinase/genetics , I-kappa B Kinase/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Rats , Rats, Inbred Lew , Tumor Necrosis Factor-alpha/metabolism
9.
J Pharmacol Exp Ther ; 317(3): 989-1001, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16525037

ABSTRACT

IkappaB kinase (IKK) beta is essential for inflammatory cytokine-induced activation of nuclear factor kappaB (NF-kappaB). NF-kappaB plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA). Here, we report the mechanism and the effect of the IKKbeta inhibitor N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a beta-carboline derivative, on NF-kappaB signaling and gene activation in RA-relevant cell systems. ML120B is a potent, selective, reversible, and ATP-competitive inhibitor of IKKbeta with an IC50 of 60 nM when evaluated in an IkappaBalpha kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentration-dependently inhibits tumor necrosis factor alpha (TNFalpha)-stimulated NF-kappaB signaling via inhibition of IkappaBalpha phosphorylation, degradation, and NF-kappaB translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast-like synoviocytes, TNFalpha- or interleukin (IL)-1beta-induced monocyte chemoattractant protein-1 regulated on activation, normal T cell expressed and secreted and production is IKKbeta-dependent. In addition, for the first time, we have demonstrated that lipopolysaccharide- or peptidoglycan-induced cytokine production in human cord blood-derived mast cells is IKKbeta-dependent. In addition, in human chondrocytes, ML120B inhibited IL-1beta-induced matrix metalloproteinase production with an IC50 of approximately 1 microM. ML120B also blocked IL-1beta-induced prostaglandin E2 production. In summary, ML120B blocked numerous NF-kappaB-regulated cell responses that are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKKbeta inhibitors as anti-inflammatory agents for the treatment of RA.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Connective Tissue Cells , Enzyme Inhibitors/pharmacology , I-kappa B Kinase/antagonists & inhibitors , NF-kappa B/antagonists & inhibitors , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Chondrocytes/drug effects , Chondrocytes/enzymology , Chondrocytes/immunology , Connective Tissue Cells/drug effects , Connective Tissue Cells/enzymology , Connective Tissue Cells/immunology , Cytokines/immunology , Dinoprostone/immunology , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Fibroblasts/drug effects , Fibroblasts/enzymology , Fibroblasts/immunology , HeLa Cells , Humans , Mast Cells/drug effects , Mast Cells/enzymology , Mast Cells/immunology , Molecular Structure , NF-kappa B/immunology , Signal Transduction/drug effects , Synovial Membrane/cytology
10.
Blood ; 107(11): 4266-73, 2006 Jun 01.
Article in English | MEDLINE | ID: mdl-16439676

ABSTRACT

The transcription factor NF-kappaB plays a central role in regulating inflammation and apoptosis, making it a compelling target for drug development. We identified a small molecule inhibitor (ML120B) that specifically inhibits IKKbeta, an Ikappa-B kinase that regulates NF-kappaB. IKKbeta and NF-kappaB are required in vivo for prevention of TNFalpha-mediated apoptosis. ML120B sensitized mouse bone marrow progenitors and granulocytes, but not mature B cells to TNFalpha killing in vitro, and induced apoptosis in vivo in the bone marrow and spleen within 6 hours of a single oral dose. In vivo inhibition of IKKbeta with ML120B resulted in depletion of thymocytes and B cells in all stages of development in the bone marrow but did not deplete granulocytes. TNF receptor-deficient mouse thymocytes and B cells were resistant to ML120B-induced depletion in vivo. Surprisingly, surviving bone marrow granulocytes expressed TNFR1 and TNFR2 after dosing in vivo with ML120B. Our results show that inhibition of IKKbeta with a small molecule in vivo leads to rapid TNF-dependent depletion of T and B cells. This observation has several implications for potential use of IKKbeta inhibitors for the treatment of inflammatory disease and cancer.


Subject(s)
I-kappa B Kinase/antagonists & inhibitors , Lymphocyte Depletion/methods , Receptors, Tumor Necrosis Factor, Type I/physiology , Animals , Apoptosis/drug effects , B-Lymphocytes/drug effects , Bone Marrow Cells/drug effects , Enzyme Inhibitors/pharmacology , Granulocytes/drug effects , Granulocytes/metabolism , Hematopoietic Stem Cells/drug effects , Mice , Mice, Knockout , Receptors, Tumor Necrosis Factor , Receptors, Tumor Necrosis Factor, Type I/deficiency , Receptors, Tumor Necrosis Factor, Type II/deficiency , Receptors, Tumor Necrosis Factor, Type II/physiology , Tumor Necrosis Factor Decoy Receptors , Tumor Necrosis Factor-alpha/pharmacology
11.
Clin Cancer Res ; 11(1): 28-40, 2005 Jan 01.
Article in English | MEDLINE | ID: mdl-15671525

ABSTRACT

Constitutive activation of the NF-kappaB pathway is required for survival of the activated B cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL). Here we show that a small molecule IkappaB kinase (IKK) inhibitor, PS-1145, and related compounds are toxic for ABC DLBCL cell lines but not for cell lines derived from the other prevalent form of DLBCL, germinal center B cell-like DLBCL. Treatment of ABC lines with these inhibitors rapidly induced a series of gene expression changes that were attributable to cessation of constitutive IKK activity, similar to changes induced by acute expression of genetic inhibitors of NF-kappaB, confirming the effectiveness and specificity of this compound. Before cell death, inhibition of IKK also induced features of apoptosis and an arrest in the G1 phase of the cell cycle. To test further the specificity of this toxicity, an inducible form of NF-kappaB was created by fusing the p65 NF-kappaB subunit with the ligand-binding domain of the estrogen receptor (p65-ERD). In the presence of tamoxifen, p65-ERD reversed the toxicity of IKK inhibition and restored expression of many NF-kappaB target genes. Another subgroup of DLBCL, primary mediastinal B-cell lymphoma (PMBL), also expresses NF-kappaB target genes, and treatment of a PMBL cell line with an IKK inhibitor was toxic and induced gene expression changes of a distinct group of NF-kappaB target genes. These studies validate the NF-kappaB pathway as a promising therapeutic target in ABC DLBCL, PMBL, and other lymphomas that depend on the activity of NF-kappaB for survival and proliferation.


Subject(s)
Gene Expression Regulation, Neoplastic , Lymphoma, B-Cell/drug therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Protein Serine-Threonine Kinases/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Apoptosis , Carbolines/pharmacology , Cell Cycle , Cell Line , Cell Line, Tumor , Cell Proliferation , Cell Survival , Dose-Response Relationship, Drug , Down-Regulation , Enzyme Inhibitors/pharmacology , Genes, Dominant , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , I-kappa B Kinase , Inhibitory Concentration 50 , L-Lactate Dehydrogenase/metabolism , Leukocytes, Mononuclear/cytology , NF-kappa B/metabolism , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Pyridines/pharmacology , Receptors, Estrogen/metabolism , Tamoxifen/pharmacology , Time Factors , Up-Regulation
12.
J Org Chem ; 61(8): 2664-2676, 1996 Apr 19.
Article in English | MEDLINE | ID: mdl-11667096

ABSTRACT

The asymmetric syntheses of heteroaromatic 3-[(tert-butyldimethylsilyl)oxy]-2-azetidinones 12-16 via chiral ester enolate-imine cyclocondensation chemistry are described. The azetidinones contain heteroaromatic moieties which, in certain cases, contribute to a decrease in enantioselectivity due to possible alternate coordinations in the transition states. The (3R,4S)-3-[(tert-butyldimethylsilyl)oxy]-4-heteroaryl-2-azetidinones were subsequently converted to the heteroaromatic taxanes 31-36 and 43-45. Conformational analyses of the 3'-(2-pyridyl) analogue 31 and 3'-(2-furyl) analogue 43 indicate they have solution conformational preferences virtually identical to paclitaxel and docetaxel. Heteroaromatic N-acyl paclitaxel analogues 47-51 were prepared from N-debenzoylpaclitaxel via Schotten-Baumann acylation. The majority of the 14 analogues displayed good to excellent activity in a microtubule assembly assay in comparison to paclitaxel. The analogues were also tested for cytotoxicity against B16 melanoma cells. 3'-Dephenyl-3'-(2-pyridyl)paclitaxel (31), 3'-dephenyl-3'-(2-furyl)paclitaxel (34), N-BOC-3'-dephenyl-3'-(2-furyl)paclitaxel (43), 3'-dephenyl-3'-(2-furyl)-N-(hexanoyl)paclitaxel (44), and N-debenzoyl-N-(3-furoyl)paclitaxel (51) were found to be more cytotoxic than paclitaxel against this cell line. 3'-Dephenyl-3'-(4-pyridyl)paclitaxel (33) and N-debenzoyl-N-(2-furoyl)paclitaxel (50) displayed cytotoxicity against B16 melanoma cells similar to paclitaxel.

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