Медицинская библиотека · Journal of medicinal chemistry · 2015

Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington's disease.

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

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Аннотация

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.

Для цитирования: 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. Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington's disease.. Journal of medicinal chemistry. 2015. DOI: 10.1021/jm501350y.

Предметные рубрики MeSH

Animals CHO Cells Cell Proliferation Cricetulus Dose-Response Relationship, Drug Enzyme Inhibitors Humans Huntington Disease Kynurenine Kynurenine 3-Monooxygenase Mice Models, Molecular Molecular Structure Pyrimidines Rats Structure-Activity Relationship

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