Inhibitors of the kynurenine pathway as neurotherapeutics: a patent review (2012–2015)

References

• Zádori D, Klivényi P, Plangár I, et al. Endogenous neuroprotection in chronic neurodegenerative disorders: with particular regard to the kynurenines. J Cell Mol Med. 2011;15:701–717.
   PubMed Web of Science ®Google Scholar
• Wolf H. The effect of hormones and vitamin B6 on urinary excretion of metabolites of the kynurenine pathway. Scand J Clin Lab Invest Suppl. 1974;136:1–186.
   PubMedGoogle Scholar
• Beadle GW, Mitchell HK, Nyc JF. Kynurenine as an intermediate in the formation of nicotinic acid from tryptophane by Neurospora. Proc Natl Acad Sci U S A. 1947;33:155–158.
   PubMed Web of Science ®Google Scholar
• Vécsei L, Szalárdy L, Fülöp F, et al. Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov. 2013;12:64–82.
   PubMed Web of Science ®Google Scholar
• Perkins MN, Stone TW. An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res. 1982;247:184–187.
   PubMed Web of Science ®Google Scholar
• Birch PJ, Grossman CJ, Hayes AG. Kynurenate and FG9041 have both competitive and non-competitive antagonist actions at excitatory amino acid receptors. Eur J Pharmacol. 1988;151:313–315.
   PubMed Web of Science ®Google Scholar
• Kessler M, Terramani T, Lynch G, et al. A glycine site associated with N-methyl-d-aspartic acid receptors: characterization and identification of a new class of antagonists. J Neurochem. 1989;52:1319–1328.
   PubMed Web of Science ®Google Scholar
• Rózsa E, Robotka H, Vécsei L, et al. The Janus-face kynurenic acid. J Neural Transm. 2008;115:1087–1091.
   PubMed Web of Science ®Google Scholar
• Hilmas C, Pereira EF, Alkondon M, et al. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci. 2001;21:7463–7473.
   PubMed Web of Science ®Google Scholar
• Marchi M, Risso F, Viola C, et al. Direct evidence that release-stimulating alpha7* nicotinic cholinergic receptors are localized on human and rat brain glutamatergic axon terminals. J Neurochem. 2002;80:1071–1078.
   PubMed Web of Science ®Google Scholar
• Stone TW. Kynurenic acid blocks nicotinic synaptic transmission to hippocampal interneurons in young rats. Eur J Neurosci. 2007;25:2656–2665.
   PubMed Web of Science ®Google Scholar
• Arnaiz-Cot JJ, González JC, Sobrado M, et al. Allosteric modulation of alpha 7 nicotinic receptors selectively depolarizes hippocampal interneurons, enhancing spontaneous GABAergic transmission. Eur J Neurosci. 2008;27:1097–1110.
   PubMed Web of Science ®Google Scholar
• Mok MH, Fricker A-C, Weil A, et al. Electrophysiological characterisation of the actions of kynurenic acid at ligand-gated ion channels. Neuropharmacology. 2009;57:242–249.
   PubMed Web of Science ®Google Scholar
• Dobelis P, Staley KJ, Cooper DC, et al. Lack of modulation of nicotinic acetylcholine alpha-7 receptor currents by kynurenic acid in adult hippocampal interneurons. PLoS One. 2012;7:e41108.
   PubMed Web of Science ®Google Scholar
• Wang J, Simonavicius N, Wu X, et al. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J Biol Chem. 2006;281:22021–22028.
   PubMed Web of Science ®Google Scholar
• Lugo-Huitrón R, Blanco-Ayala T, Ugalde-Muñiz P, et al. On the antioxidant properties of kynurenic acid: free radical scavenging activity and inhibition of oxidative stress. Neurotoxicol Teratol. 2011;33:538–547.
   PubMed Web of Science ®Google Scholar
• Eastman CL, Guilarte TR. The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine. Neurochem Res. 1990;15:1101–1107.
   PubMed Web of Science ®Google Scholar
• Dykens JA, Sullivan SG, Stern A. Oxidative reactivity of the tryptophan metabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate. Biochem Pharmacol. 1987;36:211–217.
   PubMed Web of Science ®Google Scholar
• Jhamandas K, Boegman RJ, Beninger RJ, et al. Quinolinate-induced cortical cholinergic damage: modulation by tryptophan metabolites. Brain Res. 1990;529:185–191.
   PubMed Web of Science ®Google Scholar
• De Carvalho LP, Bochet P, Rossier J. The endogenous agonist quinolinic acid and the non endogenous homoquinolinic acid discriminate between NMDAR2 receptor subunits. Neurochem Int. 1996;28:445–452.
   PubMed Web of Science ®Google Scholar
• Liu Y, Wong TP, Aarts M, et al. NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci. 2007;27:2846–2857.
   PubMed Web of Science ®Google Scholar
• Connick JH, Stone TW. Quinolinic acid effects on amino acid release from the rat cerebral cortex in vitro and in vivo. Br J Pharmacol. 1988;93:868–876.
   PubMed Web of Science ®Google Scholar
• Rios C, Santamaria A. Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem Res. 1991;16:1139–1143.
   PubMed Web of Science ®Google Scholar
• Zádori D, Klivényi P, Szalárdy L, et al. Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: novel therapeutic strategies for neurodegenerative disorders. J Neurol Sci. 2012;322:187–191.
   PubMed Web of Science ®Google Scholar
• Schwarcz R, Guidetti P, Sathyasaikumar KV, et al. Of mice, rats and men: revisiting the quinolinic acid hypothesis of Huntington’s disease. Prog Neurobiol. 2010;90:230–245.
   PubMed Web of Science ®Google Scholar
• Stone TW, Mackay GM, Forrest CM, et al. Tryptophan metabolites and brain disorders. Clin Chem Lab Med. 2003;41:852–859.
   PubMed Web of Science ®Google Scholar
• Schwarcz R, Rassoulpour A, Wu HQ, et al. Increased cortical kynurenate content in schizophrenia. Biol Psychiatry. 2001;50:521–530.
   PubMed Web of Science ®Google Scholar
• Chess AC, Simoni MK, Alling TE, et al. Elevations of endogenous kynurenic acid produce spatial working memory deficits. Schizophr Bull. 2007;33:797–804.
   PubMed Web of Science ®Google Scholar
• Zadori D, Veres G, Szalardy L, et al. Glutamatergic dysfunctioning in Alzheimer’s disease and related therapeutic targets. J Alzheimers Dis. 2014;42(Suppl 3):S177–S187.
   Google Scholar
• Baran H, Jellinger K, Deecke L. Kynurenine metabolism in Alzheimer’s disease. J Neural Transm (Vienna). 1999;106:165–181.
   PubMed Web of Science ®Google Scholar
• Potter MC, Elmer GI, Bergeron R, et al. Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior. Neuropsychopharmacology. 2010;35:1734–1742.
   PubMed Web of Science ®Google Scholar
• Braidy N, Guillemin GJ, Grant R. Effects of kynurenine pathway inhibition on NAD metabolism and cell viability in human primary astrocytes and neurons. Int J Tryptophan Res. 2011;4:29–37.
   PubMedGoogle Scholar
• De Laurentis W, Khim L, Anderson JL, et al. The second enzyme in pyrrolnitrin biosynthetic pathway is related to the heme-dependent dioxygenase superfamily. Biochemistry. 2007;46:12393–12404.
   PubMed Web of Science ®Google Scholar
• Sugimoto H, Oda S, Otsuki T, et al. Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proc Natl Acad Sci U S A. 2006;103:2611–2616.
   PubMed Web of Science ®Google Scholar
• Forouhar F, Anderson JL, Mowat CG, et al. Molecular insights into substrate recognition and catalysis by tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A. 2007;104:473–478.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Kang SA, Mukherjee T, et al. Crystal structure and mechanism of tryptophan 2,3-dioxygenase, a heme enzyme involved in tryptophan catabolism and in quinolinate biosynthesis. Biochemistry. 2007;46:145–155.
   PubMed Web of Science ®Google Scholar
• Ball HJ, Sanchez-Perez A, Weiser S, et al. Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene. 2007;396:203–213.
   PubMed Web of Science ®Google Scholar
• Metz R, Duhadaway JB, Kamasani U, et al. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 2007;67:7082–7087.
   PubMed Web of Science ®Google Scholar
• Lob S, Konigsrainer A, Schafer R, et al. Levo- but not dextro-1-methyl tryptophan abrogates the IDO activity of human dendritic cells. Blood. 2008;111:2152–2154.
   PubMed Web of Science ®Google Scholar
• Löb S, Königsrainer A, Zieker D, et al. IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother. 2009;58:153–157.
   PubMed Web of Science ®Google Scholar
• Mándi Y, Vécsei L. The kynurenine system and immunoregulation. J Neural Transm (Vienna). 2012;119:197–209.
   PubMed Web of Science ®Google Scholar
• Grozdics E, Berta L, Bajnok A, et al. B7 costimulation and intracellular indoleamine-2,3-dioxygenase (IDO) expression in peripheral blood of healthy pregnant and non-pregnant women. BMC Pregnancy Childbirth. 2014;14:306.
   PubMed Web of Science ®Google Scholar
• Kegel ME, Bhat M, Skogh E, et al. Imbalanced kynurenine pathway in schizophrenia. Int J Tryptophan Res. 2014;7:15–22.
   PubMedGoogle Scholar
• Sathyasaikumar KV, Stachowski EK, Wonodi I, et al. Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia. Schizophr Bull. 2011;37:1147–1156.
   PubMed Web of Science ®Google Scholar
• Vacchelli E, Aranda F, Eggermont A, et al. Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology. 2014;3:e957994.
   PubMed Web of Science ®Google Scholar
• Opitz CA, Litzenburger UM, Opitz U, et al. The indoleamine-2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan upregulates IDO1 in human cancer cells. PLoS One. 2011;6:e19823.
   PubMed Web of Science ®Google Scholar
• Hou D-Y, Muller AJ, Sharma MD, et al. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res. 2007;67:792–801.
   PubMed Web of Science ®Google Scholar
• Liu X, Shin N, Koblish HK, et al. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood. 2010;115:3520–3530.
   PubMed Web of Science ®Google Scholar
• Mautino MR, Jaipuri FA, Waldo J, et al. NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy [abstract]. In: Proceedings of the 104th annual meeting of the American Association for Cancer Research; 2013 Apr 6–10; Washington, DC. Philadelphia (PA): American Association for Cancer Research; 2013. Cancer Res 2013;73:Abstract nr 491. American Association for Cancer Research.
   Google Scholar
• Li M, Bolduc AR, Hoda MN, et al. The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J Immunother Cancer. 2014;2:21.
   PubMedGoogle Scholar
• Salter M, Hazelwood R, Pogson CI, et al. The effects of a novel and selective inhibitor of tryptophan 2,3-dioxygenase on tryptophan and serotonin metabolism in the rat. Biochem Pharmacol. 1995;49:1435–1442.
   PubMed Web of Science ®Google Scholar
• Dolusić E, Larrieu P, Moineaux L, et al. Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators. J Med Chem. 2011;54:5320–5334.
   PubMed Web of Science ®Google Scholar
• Pilotte L, Larrieu P, Stroobant V, et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A. 2012;109:2497–2502.
   PubMed Web of Science ®Google Scholar
• Yu D, Tao -B-B, Yang -Y-Y, et al. The IDO inhibitor coptisine ameliorates cognitive impairment in a mouse model of Alzheimer’s disease. J Alzheimers Dis. 2015;43:291–302.
   PubMed Web of Science ®Google Scholar
• Campesan S, Green EW, Breda C, et al. The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington’s disease. Curr Biol. 2011;21:961–966.
   PubMed Web of Science ®Google Scholar
• Mazarei G, Budac DP, Lu G, et al. The absence of indoleamine 2,3-dioxygenase expression protects against NMDA receptor-mediated excitotoxicity in mouse brain. Exp Neurol. 2013;249:144–148.
   PubMed Web of Science ®Google Scholar
• O’Connor JC, Lawson MA, André C, et al. Induction of IDO by bacille Calmette-Guérin is responsible for development of murine depressive-like behavior. J Immunol. 2009;182:3202–3212.
   PubMed Web of Science ®Google Scholar
• O’Connor JC, Lawson MA, André C, et al. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry. 2009;14:511–522.
   PubMed Web of Science ®Google Scholar
• Jackman KA, Brait VH, Wang Y, et al. Vascular expression, activity and function of indoleamine 2,3-dioxygenase-1 following cerebral ischaemia-reperfusion in mice. Naunyn Schmiedebergs Arch Pharmacol. 2011;383:471–481.
   PubMed Web of Science ®Google Scholar
• Han Q, Cai T, Tagle DA, et al. Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Cell Mol Life Sci. 2010;67:353–368.
   PubMed Web of Science ®Google Scholar
• Okuno E, Nakamura M, Schwarcz R. Two kynurenine aminotransferases in human brain. Brain Res. 1991;542:307–312.
   PubMed Web of Science ®Google Scholar
• Yu P, Li Z, Zhang L, et al. Characterization of kynurenine aminotransferase III, a novel member of a phylogenetically conserved KAT family. Gene. 2006;365:111–118.
   PubMed Web of Science ®Google Scholar
• Guidetti P, Amori L, Sapko MT, et al. Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain. J Neurochem. 2007;102:103–111.
   PubMed Web of Science ®Google Scholar
• Guillemin GJ, Kerr SJ, Smythe GA, et al. Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection. J Neurochem. 2001;78:842–853.
   PubMed Web of Science ®Google Scholar
• Guidetti P, Hoffman GE, Melendez-Ferro M, et al. Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry. Glia. 2007;55:78–92.
   PubMed Web of Science ®Google Scholar
• Roberts RC, Du F, McCarthy KE, et al. Immunocytochemical localization of kynurenine aminotransferase in the rat striatum: a light and electron microscopic study. J Comp Neurol. 1992;326:82–90.
   PubMed Web of Science ®Google Scholar
• Schwarcz R, Bruno JP, Muchowski PJ, et al. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012;13:465–477.
   PubMed Web of Science ®Google Scholar
• Rossi F, Garavaglia S, Montalbano V, et al. Crystal structure of human kynurenine aminotransferase II, a drug target for the treatment of schizophrenia. J Biol Chem. 2008;283:3559–3566.
   PubMed Web of Science ®Google Scholar
• Guidetti P, Okuno E, Schwarcz R. Characterization of rat brain kynurenine aminotransferases I and II. J Neurosci Res. 1997;50:457–465.
   PubMed Web of Science ®Google Scholar
• Battaglia G, Rassoulpour A, Wu HQ, et al. Some metabotropic glutamate receptor ligands reduce kynurenate synthesis in rats by intracellular inhibition of kynurenine aminotransferase II. J Neurochem. 2000;75:2051–2060.
   PubMed Web of Science ®Google Scholar
• Luchowska E, Luchowski P, Paczek R, et al. Dual effect of DL-homocysteine and S-adenosylhomocysteine on brain synthesis of the glutamate receptor antagonist, kynurenic acid. J Neurosci Res. 2005;79:375–382.
   PubMed Web of Science ®Google Scholar
• Kocki T, Luchowski P, Luchowska E, et al. L-cysteine sulphinate, endogenous sulphur-containing amino acid, inhibits rat brain kynurenic acid production via selective interference with kynurenine aminotransferase II. Neurosci Lett. 2003;346:97–100.
   PubMed Web of Science ®Google Scholar
• Pellicciari R, Rizzo RC, Costantino G, et al. Modulators of the kynurenine pathway of tryptophan metabolism: synthesis and preliminary biological evaluation of (S)-4-(ethylsulfonyl)benzoylalanine, a potent and selective kynurenine aminotransferase II (KAT II) inhibitor. ChemMedChem. 2006;1:528–531.
   PubMed Web of Science ®Google Scholar
• Passera E, Campanini B, Rossi F, et al. Human kynurenine aminotransferase II–reactivity with substrates and inhibitors. Febs J. 2011;278:1882–1900.
   PubMed Web of Science ®Google Scholar
• Pocivavsek A, Wu H-Q, Potter MC, et al. Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology. 2011;36:2357–2367.
   PubMed Web of Science ®Google Scholar
• Amori L, Guidetti P, Pellicciari R, et al. On the relationship between the two branches of the kynurenine pathway in the rat brain in vivo. J Neurochem. 2009;109:316–325.
   PubMed Web of Science ®Google Scholar
• Pellicciari R, Venturoni F, Bellocchi D, et al. Sequence variants in kynurenine aminotransferase II (KAT II) orthologs determine different potencies of the inhibitor S-ESBA. ChemMedChem. 2008;3:1199–1202.
   PubMed Web of Science ®Google Scholar
• Casazza V, Rossi F, Rizzi M. Biochemical and structural investigations on kynurenine aminotransferase II: an example of conformation-driven species-specific inhibition? Curr Top Med Chem. 2011;11:148–157.
   PubMed Web of Science ®Google Scholar
• Wu H-Q, Okuyama M, Kajii Y, et al. Targeting kynurenine aminotransferase II in psychiatric diseases: promising effects of an orally active enzyme inhibitor. Schizophr Bull. 2014;40(Suppl 2):S152–S158.
   Google Scholar
• Dounay AB, Anderson M, Bechle BM, et al. Discovery of brain-penetrant, irreversible kynurenine aminotransferase II inhibitors for schizophrenia. ACS Med Chem Lett. 2012;3:187–192.
   PubMed Web of Science ®Google Scholar
• Kozak R, Campbell BM, Strick CA, et al. Reduction of brain kynurenic acid improves cognitive function. J Neurosci. 2014;34:10592–10602.
   PubMed Web of Science ®Google Scholar
• Battie C, Verity MA. Presence of kynurenine hydroxylase in developing rat brain. J Neurochem. 1981;36:1308–1310.
   PubMed Web of Science ®Google Scholar
• Smith JR, Jamie JF, Guillemin GJ. Kynurenine-3-monooxygenase: a review of structure, mechanism, and inhibitors. Drug Discov Today. 2016;21:315–324.
   PubMed Web of Science ®Google Scholar
• Espey MG, Chernyshev ON, Reinhard JF Jr, et al. Activated human microglia produce the excitotoxin quinolinic acid. Neuroreport. 1997;8:431–434.
   PubMed Web of Science ®Google Scholar
• Erickson JB, Flanagan EM, Russo S, et al. A radiometric assay for kynurenine 3-hydroxylase based on the release of 3H2O during hydroxylation of L-[3,5-3H]kynurenine. Anal Biochem. 1992;205:257–262.
   PubMed Web of Science ®Google Scholar
• Guillemin GJ, Smith DG, Smythe GA, et al. Expression of the kynurenine pathway enzymes in human microglia and macrophages. Adv Exp Med Biol. 2003;527:105–112.
   PubMed Web of Science ®Google Scholar
• Heyes MP, Chen CY, Major EO, et al. Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. Biochem J. 1997;326(Pt 2):351–356.
   PubMed Web of Science ®Google Scholar
• Fukui S, Schwarcz R, Rapoport SI, et al. Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem. 1991;56:2007–2017.
   PubMed Web of Science ®Google Scholar
• Crozier-Reabe KR, Phillips RS, Moran GR. Kynurenine 3-monooxygenase from Pseudomonas fluorescens: substrate-like inhibitors both stimulate flavin reduction and stabilize the flavin-peroxo intermediate yet result in the production of hydrogen peroxide. Biochemistry. 2008;47:12420–12433.
   PubMed Web of Science ®Google Scholar
• Amaral M, Levy C, Heyes DJ, et al. Structural basis of kynurenine 3-monooxygenase inhibition. Nature. 2013;496:382–385.
   PubMed Web of Science ®Google Scholar
• Carpenedo R, Chiarugi A, Russi P, et al. Inhibitors of kynurenine hydroxylase and kynureninase increase cerebral formation of kynurenate and have sedative and anticonvulsant activities. Neuroscience. 1994;61:237–243.
   PubMed Web of Science ®Google Scholar
• Harris CA, Miranda AF, Tanguay JJ, et al. Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid. Br J Pharmacol. 1998;124:391–399.
   PubMed Web of Science ®Google Scholar
• Miranda AF, Boegman RJ, Beninger RJ, et al. Protection against quinolinic acid-mediated excitotoxicity in nigrostriatal dopaminergic neurons by endogenous kynurenic acid. Neuroscience. 1997;78:967–975.
   PubMed Web of Science ®Google Scholar
• Connick JH, Heywood GC, Sills GJ, et al. Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity. Gen Pharmacol. 1992;23:235–239.
   PubMedGoogle Scholar
• Russi P, Alesiani M, Lombardi G, et al. Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsions. J Neurochem. 1992;59:2076–2080.
   PubMed Web of Science ®Google Scholar
• Pellicciari R, Natalini B, Costantino G, et al. Modulation of the kynurenine pathway in search for new neuroprotective agents. Synthesis and preliminary evaluation of (m-nitrobenzoyl)alanine, a potent inhibitor of kynurenine-3-hydroxylase. J Med Chem. 1994;37:647–655.
   PubMed Web of Science ®Google Scholar
• Moroni F, Cozzi A, Peruginelli F, et al. Neuroprotective effects of kynurenine-3-hydroxylase inhibitors in models of brain ischemia. Adv Exp Med Biol. 1999;467:199–206.
   PubMed Web of Science ®Google Scholar
• Moroni F, Carpenedo R, Cozzi A, et al. Studies on the neuroprotective action of kynurenine mono-oxygenase inhibitors in post-ischemic brain damage. Adv Exp Med Biol. 2003;527:127–136.
   PubMed Web of Science ®Google Scholar
• Cozzi A, Carpenedo R, Moroni F. Kynurenine hydroxylase inhibitors reduce ischemic brain damage: studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfonamide (Ro 61-8048) in models of focal or global brain ischemia. J Cereb Blood Flow Metab. 1999;19:771–777.
   PubMed Web of Science ®Google Scholar
• Behan WM, Stone TW. Role of kynurenines in the neurotoxic actions of kainic acid. Br J Pharmacol. 2000;129:1764–1770.
   PubMed Web of Science ®Google Scholar
• Chiarugi A, Moroni F. Quinolinic acid formation in immune-activated mice: studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(−3-nitrophenyl)thiazol-2yl]-benzenesul fonamide (Ro 61-8048), two potent and selective inhibitors of kynurenine hydroxylase. Neuropharmacology. 1999;38:1225–1233.
   PubMed Web of Science ®Google Scholar
• Speciale C, Wu HQ, Cini M, et al. (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats. Eur J Pharmacol. 1996;315:263–267.
   PubMed Web of Science ®Google Scholar
• Speciale C, Cini M, Wu HQ, et al. Kynurenic acid-enhancing and anti-ischemic effects of the potent kynurenine 3-hydroxylase inhibitor FCE 28833 in rodents. Adv Exp Med Biol. 1996;398:221–227.
   PubMedGoogle Scholar
• Natalini B, Mattoli L, Pellicciari R, et al. Synthesis and activity of enantiopure (S) (m-nitrobenzoyl) alanine, potent kynurenine-3-hydroxylase inhibitor. Bioorg Med Chem Lett. 1995;5:1451–1454.
   Web of Science ®Google Scholar
• Giordani A, Pevarello P, Cini M, et al. 4-Phenyl-4-oxo-butanoic acid derivatives inhibitors of kynurenine 3-hydroxylase. Bioorg Med Chem Lett. 1998;8:2907–2912.
   PubMed Web of Science ®Google Scholar
• Pellicciari R, Amori L, Costantino G, et al. Modulation of the kynurine pathway of tryptophan metabolism in search for neuroprotective agents. Focus on kynurenine-3-hydroxylase. Adv Exp Med Biol. 2003;527:621–628.
   PubMed Web of Science ®Google Scholar
• Sapko MT, Guidetti P, Yu P, et al. Endogenous kynurenate controls the vulnerability of striatal neurons to quinolinate: implications for Huntington’s disease. Exp Neurol. 2006;197:31–40.
   PubMed Web of Science ®Google Scholar
• Muchowski PJ, Muchowski JM, Schwarcz R, et al. The J. David Gladstone Institutes, a testamentary trust established under the will of J. David Gladstone; University of Maryland. Small molecule inhibitors of kynurenine-3-monooxygenase. WO2008022286. 2008.
   Google Scholar
• Röver S, Cesura AM, Huguenin P, et al. Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase. J Med Chem. 1997;40:4378–4385.
   PubMed Web of Science ®Google Scholar
• Grégoire L, Rassoulpour A, Guidetti P, et al. Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys. Behav Brain Res. 2008;186:161–167.
   PubMed Web of Science ®Google Scholar
• Ouattara B, Belkhir S, Morissette M, et al. Implication of NMDA receptors in the antidyskinetic activity of cabergoline, CI-1041, and Ro 61-8048 in MPTP monkeys with levodopa-induced dyskinesias. J Mol Neurosci. 2009;38:128–142.
   PubMed Web of Science ®Google Scholar
• Richter A, Hamann M. The kynurenine 3-hydroxylase inhibitor Ro 61-8048 improves dystonia in a genetic model of paroxysmal dyskinesia. Eur J Pharmacol. 2003;478:47–52.
   PubMed Web of Science ®Google Scholar
• Hamann M, Sander SE, Richter A. Effects of the kynurenine 3-hydroxylase inhibitor Ro 61-8048 after intrastriatal injections on the severity of dystonia in the dt sz mutant. Eur J Pharmacol. 2008;586:156–159.
   PubMed Web of Science ®Google Scholar
• Giorgini F, Guidetti P, Nguyen Q, et al. A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nat Genet. 2005;37:526–531.
   PubMed Web of Science ®Google Scholar
• Clark CJ, Mackay GM, Smythe GA, et al. Prolonged survival of a murine model of cerebral malaria by kynurenine pathway inhibition. Infect Immun. 2005;73:5249–5251.
   PubMed Web of Science ®Google Scholar
• Rodgers J, Stone TW, Barrett MP, et al. Kynurenine pathway inhibition reduces central nervous system inflammation in a model of human African trypanosomiasis. Brain. 2009;132:1259–1267.
   PubMed Web of Science ®Google Scholar
• Zwilling D, Huang S-Y, Sathyasaikumar KV, et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell. 2011;145:863–874.
   PubMed Web of Science ®Google Scholar
• Beconi MG, Yates D, Lyons K, et al. Metabolism and pharmacokinetics of JM6 in mice: JM6 is not a prodrug for Ro-61-8048. Drug Metab Dispos. 2012;40:2297–2306.
   PubMed Web of Science ®Google Scholar
• Toledo-Sherman LM, Prime ME, Mrzljak L, et al. 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;58:1159–1183.
   PubMed Web of Science ®Google Scholar
• Guidetti P, Eastman CL, Schwarcz R. Metabolism of [5-3H]kynurenine in the rat brain in vivo: evidence for the existence of a functional kynurenine pathway. J Neurochem. 1995;65:2621–2632.
   PubMed Web of Science ®Google Scholar
• Reinhard JF Jr. Pharmacological manipulation of brain kynurenine metabolism. Ann N Y Acad Sci. 2004;1035:335–349.
   PubMed Web of Science ®Google Scholar
• Botting NP. Chemistry and neurochemistry of the kynurenine pathway of tryptophan metabolism. Chemical Society Reviews. 1995;24:401.
   Web of Science ®Google Scholar
• Walsh HA, Botting NP. Purification and biochemical characterization of some of the properties of recombinant human kynureninase. Eur J Biochem. 2002;269:2069–2074.
   PubMedGoogle Scholar
• Lima S, Khristoforov R, Momany C, et al. Crystal structure of Homo sapiens kynureninase. Biochemistry. 2007;46:2735–2744.
   PubMed Web of Science ®Google Scholar
• Walsh HA, Leslie PL, O’Shea KC, et al. 2-Amino-4-[3ʹ-hydroxyphenyl]-4-hydroxybutanoic acid; a potent inhibitor of rat and recombinant human kynureninase. Bioorg Med Chem Lett. 2002;12:361–363.
   PubMed Web of Science ®Google Scholar
• Walsh HA, O’Shea KC, Botting NP. Comparative inhibition by substrate analogues 3-methoxy- and 3-hydroxydesaminokynurenine and an improved 3 step purification of recombinant human kynureninase. BMC Biochem. 2003;4:13.
   PubMedGoogle Scholar
• Drysdale MJ, Reinhard JF. S-aryl cysteine S,S-dioxides as inhibitors of mammalian kynureninase. Bioorg Med Chem Lett. 1998;8:133–138.
   PubMed Web of Science ®Google Scholar
• Heiss C, Anderson J, Phillips RS. Differential effects of bromination on substrates and inhibitors of kynureninase from Pseudomonas fluorescens. Org Biomol Chem. 2003;1:288–295.
   PubMed Web of Science ®Google Scholar
• Foster AC, White RJ, Schwarcz R. Synthesis of quinolinic acid by 3-hydroxyanthranilic acid oxygenase in rat brain tissue in vitro. J Neurochem. 1986;47:23–30.
   PubMed Web of Science ®Google Scholar
• Malherbe P, Köhler C, Da Prada M, et al. Molecular cloning and functional expression of human 3-hydroxyanthranilic-acid dioxygenase. J Biol Chem. 1994;269:13792–13797.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Colabroy KL, Begley TP, et al. Structural studies on 3-hydroxyanthranilate-3,4-dioxygenase: the catalytic mechanism of a complex oxidation involved in NAD biosynthesis. Biochemistry. 2005;44:7632–7643.
   PubMed Web of Science ®Google Scholar
• Köhler C, Okuno E, Flood PR, et al. Quinolinic acid phosphoribosyltransferase: preferential glial localization in the rat brain visualized by immunocytochemistry. Proc Natl Acad Sci U S A. 1987;84:3491–3495.
   PubMed Web of Science ®Google Scholar
• Vescia A, Di Prisco G. Studies on purified 3-hydroxyanthranilic acid oxidase. J Biol Chem. 1962;237:2318–2324.
   PubMed Web of Science ®Google Scholar
• Guidetti P, Wu HQ, Schwarcz R. In situ produced 7-chlorokynurenate provides protection against quinolinate- and malonate-induced neurotoxicity in the rat striatum. Exp Neurol. 2000;163:123–130.
   PubMed Web of Science ®Google Scholar
• Parli CJ, Krieter P, Schmidt B. Metabolism of 6-chlorotryptophan to 4-chloro-3-hydroxyanthranilic acid: a potent inhibitor of 3-hydroxyanthranilic acid oxidase. Arch Biochem Biophys. 1980;203:161–166.
   PubMed Web of Science ®Google Scholar
• Walsh JL, Todd WP, Carpenter BK, et al. 4-Halo-3-hydroxyanthranilates are potent inhibitors of 3-hydroxyanthranilate oxygenase in the rat brain in vitro and in vivo. Adv Exp Med Biol. 1991;294:579–582.
   PubMedGoogle Scholar
• Walsh JL, Wu HQ, Ungerstedt U, et al. 4-Chloro-3-hydroxyanthranilate inhibits quinolinate production in the rat hippocampus in vivo. Brain Res Bull. 1994;33:513–516.
   PubMed Web of Science ®Google Scholar
• Yates JR, Heyes MP, Blight AR. 4-Chloro-3-hydroxyanthranilate reduces local quinolinic acid synthesis, improves functional recovery, and preserves white matter after spinal cord injury. J Neurotrauma. 2006;23:866–881.
   PubMed Web of Science ®Google Scholar
• Linderberg M. Synthesis and QSAR of substituted 3-hydroxyanthranilic acid derivatives as inhibitors of 3-hydroxyanthranilic acid dioxygenase (3-HAO). Eur J Med Chem. 1999;34:729–744.
   Web of Science ®Google Scholar
• Luthman J, Radesäter AC, Oberg C. Effects of the 3-hydroxyanthranilic acid analogue NCR-631 on anoxia-, IL-1 beta- and LPS-induced hippocampal pyramidal cell loss in vitro. Amino Acids. 1998;14:263–269.
   PubMed Web of Science ®Google Scholar
• Luthman J. Anticonvulsant effects of the 3-hydroxyanthranilic acid dioxygenase inhibitor NCR-631. Amino Acids. 2000;19:325–334.
   PubMed Web of Science ®Google Scholar
• Vallerini GP, Amori L, Beato C, et al. 2-Aminonicotinic acid 1-oxides are chemically stable inhibitors of quinolinic acid synthesis in the mammalian brain: a step toward new antiexcitotoxic agents. J Med Chem. 2013;56:9482–9495.
   PubMed Web of Science ®Google Scholar
• Neurim Pharmaceuticals (1991) Limited. Substituted aryl-indole compounds and their kynurenine/kynuramine-like metabolites as therapeutic agents. EP2664615. 2013.
   Google Scholar
• Curadev Pharma Private Ltd. Inhibitors of the kynurenine pathway. WO2014186035. 2014.
   Google Scholar
• Dominguez C, Toledo-Sherman LM, Winkler D, et al. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof. US20130029988. 2013.
   Google Scholar
• Wityak J, Toledo-Sherman LM, Dominguez C, et al. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof. US20130331370. 2013.
   Google Scholar
• Dominguez C, Toledo-Sherman LM, Courtney SM, et al. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof. WO2013016488. 2013.
   Google Scholar
• Courtney SM, Mitchell W, Brown CJ, et al. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof. WO2013033068. 2013.
   Google Scholar
• Courtney SM, Prime M, Mitchell W, et al. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof. WO2013033085. 2013.
   Google Scholar
• The J. David Gladstone Institute; University of Maryland. Small molecule inhibitors of kynurenine-3-monooxygenase. US8710237. 2014.
   Google Scholar
• The J. David Gladstone Institutes, a testamentary trust established under the will of J. David Gladstone; University of Maryland. Small molecule inhibitors of kynurenine-3-monooxygenase. US20120046324. 2012.
   Google Scholar
• CHDI Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof. WO2013151707. 2013.
   Google Scholar
• CHDI Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof. WO2015047978. 2015.
   Google Scholar
• Wityak J, Toledo-Sherman LM, Dominguez C, et al. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof. US20120329812. 2012.
   Google Scholar
• Sacco RL, DeRosa JT, Haley EC Jr, et al. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. Jama. 2001;285:1719–1728.
   PubMed Web of Science ®Google Scholar
• Stone TW. Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection. Trends Pharmacol Sci. 2000;21:149–154.
   PubMed Web of Science ®Google Scholar
• Fülöp F, Szatmári I, Vámos E, et al. Syntheses, transformations and pharmaceutical applications of kynurenic acid derivatives. Curr Med Chem. 2009;16:4828–4842.
   PubMed Web of Science ®Google Scholar