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

2015; American Chemical Society; Volume: 58; Issue: 3 Linguagem: Inglês

10.1021/jm501350y

1520-4804

Leticia Toledo‐Sherman, Michael E. Prime, Ladislav Mrzljak, Maria Beconi, Alan Beresford, Frederick A. Brookfield, Christopher J. Brown, Isabell Cardaun, Stephen M. Courtney, Ulrike Dijkman, Estelle Hamelin-Flegg, Peter Johnson, Valerie R. Kempf, Kathy Lyons, Kimberly Matthews, William L. Mitchell, Catherine M. O’Connell, Paula Pena, Kendall D. Powell, Arash Rassoulpour, Laura Reed, Wolfgang Reindl, Suganathan Selvaratnam, Weslyn W. Friley, Derek Weddell, Naomi E. Went, Patricia Wheelan, Christin Winkler, Dirk Winkler, John Wityak, Christopher J. Yarnold, Dawn Yates, Ignacio Muñoz-Sanjuán, Celia Dominguez,

Stress Responses and Cortisol

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.