Benzoylalanine Analogues as Inhibitors of Rat Brain Kynureninase and Kynurenine 3-Hydroxylase

Giordani, Antonio; Corti, Luca; Cini, M.; Pillan, Antonio; Ferrario, R.G.; Schwarcz, Robert; Guidetti, Paolo; Speciale, C.; Varasi, Mario

doi:10.1007/978-1-4613-0381-7_77

Cited by 5 publications

(2 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The high affinity of the 3-nitro compound ( 11 ) (IC 50 = 0.05 μM), however, may indicate that these substituents do not target a truly lipophilic site in the enzyme. The high affinity of 3-nitro and 3,4-dichloro compound is a surprising coincidence with the SAR of benzoylalanine-type inhibitors of kynurenine 3-hydroxylase , and may suggest a common binding site for sulfonamide- and benzoylalanine-type inhibitors. Support for this notion comes from kinetic analysis of the mode of inhibition of 16 (Figure ) and FCE 28833 (not shown), both of which behaved as competitive inhibitors of kynurenine 3-hydroxylase with K i values of 4.8 ± 2.1 and 95 ± 27 nM, respectively.…”

Section: Resultsmentioning

confidence: 88%

Synthesis and Biochemical Evaluation ofN-(4-Phenylthiazol-2-yl)benzenesulfonamides as High-Affinity Inhibitors of Kynurenine 3-Hydroxylase

et al. 1997

View full text Add to dashboard Cite

In this paper we describe the synthesis, structure-activity relationship (SAR), and biochemical characterization of N-(4-phenylthiazol-2-yl)benzenesulfonamides as inhibitors of kynurenine 3-hydroxylase. The compounds 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide 16 (IC50 = 37 nM, Ro-61-8048) and 4-amino-N-[4-[2-fluoro-5-(trifluoromethyl)phenyl]-thiazol-2-yl] benzenesulfonamide 20 (IC50 = 19 nM) were found to be high-affinity inhibitors of this enzyme in vitro. In addition, both compounds blocked rat and gerbil kynurenine 3-hydroxylase after oral administration, with ED50's in the 3-5 mumol/kg range in gerbil brain. In a microdialysis experiment in rats, 16 dose dependently increased kynurenic acid concentration in the extracellular hippocampal fluid. A dose of 100 mumol/kg po led to a 7.5-fold increase in kynurenic acid outflow. These new compounds should allow detailed investigation of the pathophysiological role of the kynurenine pathway after neuronal injury.

show abstract

Section: Resultsmentioning

confidence: 88%

Synthesis and Biochemical Evaluation ofN-(4-Phenylthiazol-2-yl)benzenesulfonamides as High-Affinity Inhibitors of Kynurenine 3-Hydroxylase

et al. 1997

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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...

show abstract

Modulation of the Kynurenine Pathway for the Potential Treatment of Neurodegenerative Diseases

Courtney

Scheel

2010

Topics in Medicinal Chemistry

View full text Add to dashboard Cite

Benzoylalanine Analogues as Inhibitors of Rat Brain Kynureninase and Kynurenine 3-Hydroxylase

Cited by 5 publications

References 12 publications

Synthesis and Biochemical Evaluation ofN-(4-Phenylthiazol-2-yl)benzenesulfonamides as High-Affinity Inhibitors of Kynurenine 3-Hydroxylase

Synthesis and Biochemical Evaluation ofN-(4-Phenylthiazol-2-yl)benzenesulfonamides as High-Affinity Inhibitors of Kynurenine 3-Hydroxylase

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

Modulation of the Kynurenine Pathway for the Potential Treatment of Neurodegenerative Diseases

Contact Info

Product

Resources

About