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

ABSTRACT

Introduction: The proven pathological alterations in the kynurenine pathway of tryptophan metabolism, either in preclinical models of neurological and psychiatric disorders or in human samples themselves, elicited numerous attempts to restore the altered balance via pharmaceutical manipulation of the pathway.

Areas covered: The aim of the authors was to conduct a review of relevant scientific data on enzyme inhibitors of the kynurenine pathway, with special attention to pipeline drug development strategies based on relevant patent literature, covering the period of 2012–2015. Considering the magnitude of the topic, only the most prominent examples of lead compounds and substances necessary to enlighten structure activity relationships were reported.

Expert opinion: Although the clinical and preclinical data are reassuring, there is a lack of applicable drugs in daily clinical practice. However, the recent determination of enzyme structures considerably promoted the development of potent inhibitors, most of them having been designed as a structural analog of the natural enzyme substrate. Especially, the inhibition of indolamine 2,3-dioxygenase in central nervous system tumors, the inhibition of kynurenine aminotransferase in cognitive dysfunction, and the inhibition of kynurenine 3-monooxygenase in neurodegenerative disorders, such as Huntington’s disease, each show great promise.

KEYWORDS:

• Inhibitors
• kynurenine pathway
• neurotherapeutics
• tryptophan metabolism

Article highlights

• The kynurenine pathway of tryptophan metabolism serves as an interesting drug target in certain neurological and psychiatric conditions.

• Amongst therapeutic options, the development of enzyme inhibitors would be one of the leading options for pharmaceutical manipulation of pathological alterations.

• In light of preclinical data, especially the inhibitors of indolamine 2,3-dioxygenase, kynurenine aminotransferase and kynurenine 3-monooxygenase could exert beneficial effects in future clinical studies.

• Probably the most extensively studied field is that of the kynurenine 3-monooxygenase inhibitors, highlighting the lead compounds of trans-2-substituted-cyclopropane-1-carboxylic acids, phenylthiazole, phenylthiadiazole and pyrimidine benzenesulfonamides, and aryl pyrimidines.

• The reassuring preclinical data warrant future well-designed clinical studies to enable the identification of compounds that may provide relief in some devastating neurological and psychiatric illnesses.

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Declaration of interest

This work was supported by the projects MTA-SZTE Neuroscience Research Group, Hungarian Brain Research Programs – Grant No. KTIA_NAP_13-A_III/9. and Grant No. KTIA_NAP_13-A_II/18., OTKA (K 105077) and EUROHEADPAIN-FP7-Health-2013-Innovation – Grant No. 602633. Dénes Zádori was supported by the Bolyai Scholarship Program of the Hungarian Academy of Sciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.