Development of a Series of Aryl Pyrimidine Kynurenine Monooxygenase Inhibitors as Potential Therapeutic Agents for the Treatment of Huntington’s Disease

We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 58; no. 3; pp. 1159 - 1183
Main Authors:	Toledo-Sherman, Leticia M, Prime, Michael E, Mrzljak, Ladislav, Beconi, Maria G, Beresford, Alan, Brookfield, Frederick A, Brown, Christopher J, Cardaun, Isabell, Courtney, Stephen M, Dijkman, Ulrike, Hamelin-Flegg, Estelle, Johnson, Peter D, Kempf, Valerie, Lyons, Kathy, Matthews, Kimberly, Mitchell, William L, O’Connell, Catherine, Pena, Paula, Powell, Kendall, Rassoulpour, Arash, Reed, Laura, Reindl, Wolfgang, Selvaratnam, Suganathan, Friley, Weslyn Ward, Weddell, Derek A, Went, Naomi E, Wheelan, Patricia, Winkler, Christin, Winkler, Dirk, Wityak, John, Yarnold, Christopher J, Yates, Dawn, Munoz-Sanjuan, Ignacio, Dominguez, Celia
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 12-02-2015
Subjects:	Animals Cell Proliferation - drug effects CHO Cells Cricetulus Dose-Response Relationship, Drug Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Huntington Disease - drug therapy Huntington Disease - metabolism Kynurenine - metabolism Kynurenine 3-Monooxygenase - antagonists & inhibitors Kynurenine 3-Monooxygenase - metabolism Mice Models, Molecular Molecular Structure Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Rats Structure-Activity Relationship
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Summary:	We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm501350y