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Your search keyword '"Wishart N"' showing total 5 results
Start Over Author "Wishart N" Publisher elsevier science ltd
5 results on '"Wishart N"'

1. Structure activity optimization of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines as Jak1 kinase inhibitors.

Author

Friedman M, Frank KE, Aguirre A, Argiriadi MA, Davis H, Edmunds JJ, George DM, George JS, Goedken E, Fiamengo B, Hyland D, Li B, Murtaza A, Morytko M, Somal G, Stewart K, Tarcsa E, Van Epps S, Voss J, Wang L, Woller K, and Wishart N

Subjects
Animals, Cell Line, Dose-Response Relationship, Drug, Humans, Janus Kinase 1 metabolism, Male, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyrazines chemical synthesis, Pyrazines chemistry, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles chemistry, Janus Kinase 1 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Pyrazines pharmacology, Triazoles pharmacology
Abstract

Previous work investigating tricyclic pyrrolopyrazines as kinase cores led to the discovery that 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (12) had Jak inhibitory activity. Herein we describe our initial efforts to develop orally bioavailable analogs of 12 with improved selectivity of Jak1 over Jak2., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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2. Design and synthesis of tricyclic cores for kinase inhibition.

Author

Van Epps S, Fiamengo B, Edmunds J, Ericsson A, Frank K, Friedman M, George D, George J, Goedken E, Kotecki B, Martinez G, Merta P, Morytko M, Shekhar S, Skinner B, Stewart K, Voss J, Wallace G, Wang L, Wang L, and Wishart N

Subjects
Cells, Cultured, Cyclization, Enzyme Activation drug effects, Inhibitory Concentration 50, Molecular Structure, Pyrazines chemical synthesis, Pyrazines chemistry, Pyrazines pharmacology, Pyridines chemical synthesis, Pyridines chemistry, Pyridines pharmacology, Pyrroles chemical synthesis, Pyrroles chemistry, Pyrroles pharmacology, Drug Design, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology
Abstract

Interest in therapeutic kinase inhibitors continues to grow beyond success in oncology. To date, ATP-mimetic kinase inhibitors have focused primarily on monocyclic and bicyclic heterocyclic cores. We sought to expand on the repertoire of potential cores for kinase inhibition by exploring tricyclic variants of classical bicyclic hinge binding motifs such as pyrrolopyridine and pyrrolopyrazine. Herein we describe the syntheses of eight alternative tricyclic cores as well as in vitro screening results for representative kinases of potential therapeutic interest., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2013
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3. 2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization.

Author

Harris CM, Ericsson AM, Argiriadi MA, Barberis C, Borhani DW, Burchat A, Calderwood DJ, Cunha GA, Dixon RW, Frank KE, Johnson EF, Kamens J, Kwak S, Li B, Mullen KD, Perron DC, Wang L, Wishart N, Wu X, Zhang X, Zmetra TR, and Talanian RV

Subjects
Administration, Oral, Animals, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents pharmacokinetics, Binding Sites, Computer Simulation, Crystallography, X-Ray, Humans, Intracellular Signaling Peptides and Proteins metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacokinetics, Protein Serine-Threonine Kinases metabolism, Pyrimidines chemical synthesis, Pyrimidines pharmacokinetics, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Tumor Necrosis Factor-alpha metabolism, Anti-Inflammatory Agents chemistry, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrimidines chemistry
Abstract

We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC(50) values as low as 19nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFalpha production in peripheral human monocytes., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Published
2010
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4. Identification of a selective thieno[2,3-c]pyridine inhibitor of COT kinase and TNF-alpha production.

Author

Cusack K, Allen H, Bischoff A, Clabbers A, Dixon R, Fix-Stenzel S, Friedman M, Gaumont Y, George D, Gordon T, Grongsaard P, Janssen B, Jia Y, Moskey M, Quinn C, Salmeron A, Thomas C, Wallace G, Wishart N, and Yu Z

Subjects
Animals, Arthritis, Rheumatoid drug therapy, Chemistry, Pharmaceutical methods, Drug Design, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, Hydrogen Bonding, Inhibitory Concentration 50, Interleukin-1beta metabolism, Ligands, MAP Kinase Kinase Kinases chemistry, Mice, Molecular Structure, Proto-Oncogene Proteins chemistry, Pyridines pharmacology, Tumor Necrosis Factor-alpha chemistry, Tumor Necrosis Factor-alpha metabolism, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, MAP Kinase Kinase Kinases antagonists & inhibitors, Proto-Oncogene Proteins antagonists & inhibitors, Pyridines chemical synthesis, Tumor Necrosis Factor-alpha antagonists & inhibitors
Abstract

COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-alpha and other pro-inflammatory cytokines such as IL-1beta via the ERK/MAP kinase pathway. As TNF-alpha and IL-1beta are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase.

Published
2009
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5. Discovery of thieno[2,3-c]pyridines as potent COT inhibitors.

Author

George D, Friedman M, Allen H, Argiriadi M, Barberis C, Bischoff A, Clabbers A, Cusack K, Dixon R, Fix-Stenzel S, Gordon T, Janssen B, Jia Y, Moskey M, Quinn C, Salmeron JA, Wishart N, Woller K, and Yu Z

Subjects
Combinatorial Chemistry Techniques, Crystallography, X-Ray, Humans, Molecular Conformation, Molecular Structure, Pyridines chemistry, Structure-Activity Relationship, Thiophenes chemistry, MAP Kinase Kinase Kinases antagonists & inhibitors, Models, Molecular, Proto-Oncogene Proteins antagonists & inhibitors, Pyridines chemical synthesis, Pyridines pharmacology, Thiophenes chemical synthesis, Thiophenes pharmacology
Abstract

Evaluation of hit chemotypes from high throughput screening identified a novel series of 2,4-disubstituted thieno[2,3-c]pyridines as COT kinase inhibitors. Structural modifications exploring SAR at the 2- and 4-positions resulting in inhibitors with improved enzyme potency and cellular activity are disclosed.

Published
2008
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