4-Phenyl-4-oxo-butanoic acid derivatives inhibitors of kynurenine 3-hydroxylase

Giordani, Antonio; Pevarello, Paolo; Cini, M.; Bormetti, R.; Greco, Felicita; Toma, Salvatore; Speciale, C.; Varasi, Mario

doi:10.1016/s0960-894x(98)00517-4

Cited by 27 publications

(14 citation statements)

References 12 publications

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“…Systematic evaluation of structure-activity relationships, varying either the aromatic ring region (Giordani et al, 1996) or the side chain (Giordani et al, 1998), revealed that the 2-amino group of the benzoylalanine moiety was not necessary for enzyme inhibition, with 11 exhibiting high activity . Conformational restriction of the side chain turned out to be the key to obtaining the first competitive inhibitor of kynurenine 3-hydroxylase that was active in the nanomolar range.…”

Section: Enzymes Regulating the Kyna/quin Balancementioning

confidence: 99%

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

Schwarcz

Pellicciari²

2002

J Pharmacol Exp Ther

500

418

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Degradation of the essential amino acid tryptophan along the kynurenine pathway (KP) yields several neuroactive intermediates, including the free radical generator 3-hydroxykynurenine, the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid, and the NMDA and ␣7 nicotinic acetylcholine receptor antagonist kynurenic acid. The ambient levels of these compounds are determined by several KP enzymes, which in the brain are preferentially localized in astrocytes and microglial cells. Normal fluctuations in the brain levels of neuroactive KP intermediates might modulate several neurotransmitter systems. Impairment of KP metabolism is functionally significant and occurs in a variety of diseases that affect the brain. Pharmacological agents targeting specific KP enzymes are now available to manipulate the concentration of neuroactive KP intermediates in the brain. These compounds can be used to normalize KP defects, show remarkable efficacy in animal models of central nervous system disorders, and offer novel therapeutic opportunities. Neuroactive Tryptophan MetabolitesIn mammals, the vast majority of dietary tryptophan is metabolized via the kynurenine pathway (KP) (Scheme 1), which is initiated by the oxidative opening of the indole ring and eventually produces the ubiquitous enzyme cofactor NAD ϩ . This catabolic cascade is notable for the fact that it contains three neuroactive intermediates, all of which derive directly or indirectly from L-kynurenine (L-KYN), the primary major degradation product of tryptophan. One of the three compounds, kynurenic acid (KYNA), is formed in a "dead end" side-arm of the pathway, whereas the other two, 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN), are synthesized from L-KYN en route to NAD ϩ . Although all kynurenines-the collective term used for KP intermediates shown in Scheme 1-are found in high concentration in urine (hence the name), none of them has so far been assigned an important physiological function in peripheral organs.The first indication that kynurenines might play a role in the brain was provided by Lapin (1978), who noted convulsions after an intracerebroventricular QUIN injection in mice. Soon thereafter, ionophoretically applied QUIN was found to excite rat cortical neurons (Stone and Perkins, 1981), and intracerebrally injected QUIN was shown to cause excitotoxic lesions in rat brain (Schwarcz et al., 1983). Both QUIN-induced excitation and neurotoxicity are mediated by N-methyl-D-aspartate (NMDA) receptors, leading to the suggestion that endogenous QUIN might participate in physiological and pathological processes that are associated with NMDA receptor activation. Indeed, QUIN occurs naturally in the mammalian brain, although the low QUIN content of cerebral tissue (50 -1000 nM) is difficult to reconcile with its low receptor affinity (ED 50 Ͼ100 M). It appears that the remarkably high in vivo potency of QUIN, particularly as an excitotoxin, is caused by a combination of factors, including the absence of effective removal mech...

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Section: Enzymes Regulating the Kyna/quin Balancementioning

confidence: 99%

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

Schwarcz

Pellicciari²

2002

J Pharmacol Exp Ther

500

418

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“…Compound 18 (PNU 156561, formerly known as FCE 28833A; (R,S)-3,4-dichlorobenzoylalanine) is also capable of exerting anti-ischemic effects, probably via increasing brain KYNA levels [102,103]. With regard to SAR studies in benzoylalanines, it can be concluded that the S-enantiomers would be are more potent (IC 50 = 500 nM [104]), the carboxyl group is obligatory for inhibition, whereas the amine group is not [105]. Therefore the amine can be replaced with a methylene bridge, resulting in compound 19 (UPF 648;…”

Section: Kynurenine Aminotransferasesmentioning

confidence: 99%

“…However, the addition of 16 to L-KYN and probenecid increased the potency to protect against QUIN-mediated neurotoxicity in the striatum [92]and in the nigrostriatal dopaminergic system [93]. Furthermore, 16has can be concluded that the S-enantiomers would be are more potent (IC 50 = 500 nM[104]), the carboxyl group is obligatory for inhibition, whereas the amine group is not [105]. Therefore the amine can be replaced with a methylene bridge, resulting in compound 19 (UPF 648;…”

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confidence: 99%

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

Zádori

Veres

Szalárdy

et al. 2016

Expert Opinion on Therapeutic Patents

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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 a 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 enlight 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 have 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, alike provide a great promise. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 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 optionsforin 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-substitutedcyclopropane-1-carboxylic acids, phenylthiazole, phenylthiadiazole and pyrimidine benzenesulfonamides, and aryl pyrimidines.• The reassuring preclinical data warrant future well-designed clinical studies to beenable to determine which the identification of compounds that may provide relief in some devastating neurological and psychiatric illnesses. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24...

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“…There are some isolated reports on the Friedel–Crafts acylation reaction of α‐acetoxybutendioic anhydride ( 2a ). Pevarello et al10 and Mi et al11 reported the Friedel–Crafts acylation of 2a with 1,2‐dichlorobenzene and benzene, respectively, under reflux conditions. In both of these reactions, the anhydride carbonyl group participated in the acylation reaction in the presence of an ester carbonyl group to form the corresponding α‐hydroxy keto acid.…”

Section: Introductionmentioning

confidence: 99%