title: Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington's disease.
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.
authors.affiliation: Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, U.K.
authors.forename: Leticia M
authors.initials: LM
authors.lastname: Toledo-Sherman
authors.forename: Michael E
authors.initials: ME
authors.lastname: Prime
authors.forename: Ladislav
authors.initials: L
authors.lastname: Mrzljak
authors.forename: Maria G
authors.initials: MG
authors.lastname: Beconi
authors.forename: Alan
authors.initials: A
authors.lastname: Beresford
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Brookfield
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Brown
authors.forename: Isabell
authors.initials: I
authors.lastname: Cardaun
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Courtney
authors.forename: Ulrike
authors.initials: U
authors.lastname: Dijkman
authors.forename: Estelle
authors.initials: E
authors.lastname: Hamelin-Flegg
authors.forename: Peter D
authors.initials: PD
authors.lastname: Johnson
authors.forename: Valerie
authors.initials: V
authors.lastname: Kempf
authors.forename: Kathy
authors.initials: K
authors.lastname: Lyons
authors.forename: Kimberly
authors.initials: K
authors.lastname: Matthews
authors.forename: William L
authors.initials: WL
authors.lastname: Mitchell
authors.forename: Catherine
authors.initials: C
authors.lastname: O'Connell
authors.forename: Paula
authors.initials: P
authors.lastname: Pena
authors.forename: Kendall
authors.initials: K
authors.lastname: Powell
authors.forename: Arash
authors.initials: A
authors.lastname: Rassoulpour
authors.forename: Laura
authors.initials: L
authors.lastname: Reed
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Reindl
authors.forename: Suganathan
authors.initials: S
authors.lastname: Selvaratnam
authors.forename: Weslyn Ward
authors.initials: WW
authors.lastname: Friley
authors.forename: Derek A
authors.initials: DA
authors.lastname: Weddell
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Went
authors.forename: Patricia
authors.initials: P
authors.lastname: Wheelan
authors.forename: Christin
authors.initials: C
authors.lastname: Winkler
authors.forename: Dirk
authors.initials: D
authors.lastname: Winkler
authors.forename: John
authors.initials: J
authors.lastname: Wityak
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Yarnold
authors.forename: Dawn
authors.initials: D
authors.lastname: Yates
authors.forename: Ignacio
authors.initials: I
authors.lastname: Munoz-Sanjuan
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
mesh_terms: D000818:Animals; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D007737:Kynurenine; D050601:Kynurenine 3-Monooxygenase; C030986:pyrimidine