- Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntingtons disease
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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.
- 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.,Oconnell, 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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p. 1159 - 1183
(2015/03/04)
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- 1-Aryl-2-((6-aryl)pyrimidin-4-yl)amino)ethanols as competitive inhibitors of fatty acid amide hydrolase
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A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain.
- Keith, John M.,Hawryluk, Natalie,Apodaca, Richard L.,Chambers, Allison,Pierce, Joan M.,Seierstad, Mark,Palmer, James A.,Webb, Michael,Karbarz, Mark J.,Scott, Brian P.,Wilson, Sandy J.,Luo, Lin,Wennerholm, Michelle L.,Chang, Leon,Rizzolio, Michele,Chaplan, Sandra R.,Breitenbucher, J. Guy
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p. 1280 - 1284
(2014/03/21)
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- ETHYLENE DIAMINE MODULATORS OF FATTY ACID AMIDE HYDROLASE
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Certain ethylene diamine compounds of Formula (I) are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, energy metabolism disorders, and movement disorders (e.g., multiple sclerosis). Methods of synthesizing such compounds are also disclosed.
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Page/Page column 33
(2011/04/13)
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- ARYL-HYDROXYETHYLAMINO-PYRIMIDINES AND TRIAZINES AS MODULATORS OF FATTY ACID AMIDE HYDROLASE
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Certain aryl-hydroxyethylamino-pyrimidine and triazine compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, energy metabolism disorders, and movement disorders (e.g., multiple sclerosis). Methods of synthesizing such compounds are also disclosed.
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Page/Page column 42
(2009/10/18)
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