Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia

Dounay, Amy B.; Anderson, Marie; Bechle, Bruce M.; Campbell, Brian; Claffey, Michelle M.; Evdokimov, A.G.; Evrard, Edelweiss; Fonseca, Kari R.; Gan, Xinmin; Ghosh, Shalini; Hayward, Matthew M.; Horner, W. Elliott; Kim, Jiyoung; McAllister, Laura A.; Pandit, J.; Paradis, Vanessa; Parikh, Vinod D.; Reese, Matthew R.; Rong, Suo-Bao; Salafia, Michelle A.; Schuyten, Katherine; Strick, Christine A.; Tuttle, Jamison B.; Valentine, James J.; Wang, Hong; Zawadzke, Laura E.

doi:10.1021/ml200204m

Cited by 83 publications

(59 citation statements)

References 31 publications

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“…A rather small decrease in brain KYNA induced by acute KAT II inhibition in the rodent brain is sufficient to induce pro-cognitive effects (Kozak et al, 2014; Pocivavsek et al, 2011; Wu et al, 2014). These pre-clinical studies show promise for the translatability of KAT II inhibition clinically as two orally active compounds, BFF-816 (Pocivavsek et al, 2014b; Wu et al, 2014) and PF-04859989 (Dounay et al, 2012; Kozak et al, 2014), readily overcome contextual memory, working memory, spatial memory, and sustained attention deficits in models relevant to the study of SZ preclinically.…”

Section: Implications For Interventions In Psychiatric Disordersmentioning

confidence: 97%

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

Notarangelo

Pocivavsek

2017

Neuropharmacology

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The kynurenine pathway (KP) of tryptophan degradation contains several neuroactive metabolites that may influence brain function in health and disease. Mounting focus has been dedicated to investigating the role of these metabolites during neurodevelopment and elucidating their involvement in the pathophysiology of psychiatric disorders with a developmental component, such as schizophrenia. In this review, we describe the changes in KP metabolism in the brain from gestation until adulthood and illustrate how environmental and genetic factors affect the KP during development. With a particular focus on kynurenic acid, the antagonist of α7 nicotinic acetylcholine (α7nACh) and N-methyl-D-aspartate (NMDA) receptors, both implicated in modulating brain development, we review animal models designed to ascertain the role of perinatal KP elevation on long-lasting biochemical, neuropathological, and behavioral deficits later in life. We present new data demonstrating that combining perinatal choline-supplementation, to potentially increase activation of α7nACh receptors during development, with embryonic kynurenine manipulation is effective in attenuating cognitive impairments in adult rat offspring. With these findings in mind, we conclude the review by discussing the advancement of therapeutic interventions that would target not only symptoms, but potentially the root cause of central nervous system diseases that manifest from a perinatal KP insult.

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Section: Implications For Interventions In Psychiatric Disordersmentioning

confidence: 97%

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

Notarangelo

Pocivavsek

2017

Neuropharmacology

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“…The next generation of hKAT2 inhibitors were BFF-122 and the cyclic hydroxamic acid PF-04859989, which were identified as potent and irreversible inhibitors of human KAT II with reported IC 50 s of around 0.1 to 1 µM [18]. The mechanism of action of these inhibitors is by inactivating PLP irreversibly, and hence providing the knock down of KAT2-however irreversible inhibitors are generally not optimal in drug design and development [19]. Moreover, Schwarcz and others have recently shown the superior application of the reversible inhibition by using BFF-816 in preclinical trials [20].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, in order to comprehensively study KAT-2 inhibitors, the inhibitory activities of the designed compound along with several other reported KAT-2 inhibitors were evaluated using our HPLC based inhibition assay. Meanwhile, by means of HPLC and surface plasmon resonance (SPR) techniques, the probable mechanism of action and binding was identified and described in comparison with PF-04859989, a well-established irreversible KAT-2 inhibitor [19].…”

Section: Introductionmentioning

confidence: 99%

Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders

et al. 2016

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Abnormal levels of kynurenic acid (KYNA) in the human brain are believed to be connected to several central nervous system (CNS) diseases, therefore compounds which affect the production of this crucial metabolite are of interest in CNS drug development. The majority of KYNA production is accounted for by kynurenine aminotransferase-2 (KAT-2) in the mammalian brain; hence this enzyme is one of the most interesting targets with which to modulate KYNA levels. Recently developed human KAT-2 inhibitors with high potencies are known to irreversibly bind to the enzyme cofactor, pyridoxal-5 1 -phosphate (PLP), which may lead to severe side effects due to the abundance of PLP-dependent enzymes. In this study, we report a reversible and competitive inhibitor of KAT-2. Its inhibitory activities were examined using HPLC and surface plasmon resonance (SPR) and compare favorably with other recently reported KAT-2 inhibitors. Our inhibitor, NS-1502, demonstrates suitable inhibitory activity, almost 10 times more potent than the known reversible KAT-2, (S)-ESBA.

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“…140 It has a clean CEREP panel profile and is highly selective for KATII versus KATI, III, and IV isoforms. Similar to 53, 54 forms a covalent bond with PLP, leading to a highly potent complex that has a robust pharmacodynamic effect on KYNA levels in the brain.…”

Section: Figure 19 Early Examples Of Kat II Inhibitorsmentioning

confidence: 99%

Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway

2015

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The kynurenine pathway is responsible for the metabolism of more than 95% of dietary tryptophan (TRP) and produces numerous bioactive metabolites. Recent studies have focused on three enzymes in this pathway: indoleamine dioxygenase (IDO1), kynurenine monooxygenase (KMO), and kynurenine aminotransferase II (KAT II). IDO1 inhibitors are currently in clinical trials for the treatment of cancer, and these agents may also have therapeutic utility in neurological disorders, including multiple sclerosis. KMO inhibitors are being investigated as potential treatments for neurodegenerative diseases, such as Huntington's and Alzheimer's diseases. KAT II inhibitors have been proposed in new therapeutic approaches toward psychiatric and cognitive disorders, including cognitive impairment associated with schizophrenia. Numerous medicinal chemistry studies are currently aimed at the design of novel, potent, and selective inhibitors for each of these enzymes. The emerging opportunities and significant challenges associated with pharmacological modulation of these enzymes will be explored in this review.

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Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia

Cited by 83 publications

References 31 publications

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders

Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway

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