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

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

  • J Med Chem. 2015 Feb 12;58(3):1159-83. doi: 10.1021/jm501350y.
Leticia M Toledo-Sherman 1,  Michael E Prime,  Ladislav Mrzljak,  Maria G Beconi,  Alan Beresford,  Frederick A Brookfield,  Christopher J Brown,  Isabell Cardaun,  Stephen M Courtney,  Ulrike Dijkman,  Estelle Hamelin-Flegg,  Peter D Johnson,  Valerie Kempf,  Kathy Lyons,  Kimberly Matthews,  William L Mitchell,  Catherine O'Connell,  Paula Pena,  Kendall Powell,  Arash Rassoulpour,  Laura Reed,  Wolfgang Reindl,  Suganathan Selvaratnam,  Weslyn Ward Friley,  Derek A Weddell,  Naomi E Went,  Patricia Wheelan,  Christin Winkler,  Dirk Winkler,  John Wityak,  Christopher J Yarnold,  Dawn Yates,  Ignacio Munoz-Sanjuan,  Celia Dominguez
Affiliations

Affiliation

  • 1 Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, U.K.
PMID: 25590515 DOI: 10.1021/jm501350y
Abstract

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.

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