Derivatives of kynurenine as inhibitors of rat brain kynurenine aminotransferase

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

“…We also compare 6 with d,l-5-Cl-KYN (7) and l-5-Cl-KYN (8), which are two known KAT inhibitors. [13] Finally, we show that the new benzoylalanine derivative, but not l-5-Cl-KYN (8), effectively decreases brain KYNA concentrations in vivo. This difference between the two compounds is explained in terms of their properties as KP enzyme inhibitors.…”

“…So far, however, only a few potent KAT inhibitors have been described. [13] During the past years, we and others have shown that the benzoylalanine nucleus is particularly amenable to decoration, resulting in potent and selective kynurenine 3-hydroxylase inhibitors such as NAL, mNBA, and FCE 28833. [14,15] In the frame of this project, we recently became interested in the synthesis of sulfonylalkyl-substituted benzoylalanine derivatives, with the aim of taking advantage of the versatility of this moiety for its size, hydrophobic/hydrophilic balance, and capacity for accepting hydrogen bonds.…”

“…The synthetic protocol for the preparation of the racemic benzoylalanine derivative 5 (Scheme 2) involved classical acetamidomalonate addition/decarboxylative hydrolysis as the key step for the generation of the amino acidic moiety starting from 4-ethylsulfonyl-a-bromoacetophenone (11), [13] prepared in two steps from commercially available 4-acetyl-benzenesulfonyl chloride (9). Thus, 9 treated with sodium sulfite in basic aqueous conditions yielded the corresponding sodium sulfinate, which, by subsequent addition of 1-bromoethane, furnished the corresponding 4-ethylsulfonylacetophenone derivative 10 in 40 % yield.…”

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

“…Although the precise mechanism controlling the release of KYNA has not been elucidated, this insight led to the development of specific KAT-II inhibitors, which are designed to target astrocytes and reduce extracellular KYNA concentrations. From the outset, these agents were not only viewed as tools to study the neurobiology of KYNA, but were also appreciated for their potential therapeutic applications (Schwarcz and Pellicciari, 2002;Varasi et al, 1996). ESBA, which was used in the present study, was introduced as the first specific KAT-II inhibitor in 2006 (Pellicciari et al, 2006).…”

Sequence Variants in Kynurenine Aminotransferase II (KAT II) Orthologs Determine Different Potencies of the Inhibitor S‐ESBA

“…[10,12,13] The development of KAT inhibitors may prove useful in disorders associated with learning and memory deficits, where lowering the levels of brain KYNA may counterbalance glutamatergic and cholinergic hypofunction. [3,14] Recently, we reported the synthesis and biological characterization of (S)-4-ethylsulfonylbenzoylalanine (S-ESBA, 5), the first potent and selective inhibitor of KAT II, which is the dominant KYNA-forming enzyme in the rat brain. [15] Biological assays conducted in vitro showed that S-ESBA (5) inhibits KAT II obtained from partially purified rat liver with an IC 50 value of 6.1 mm.…”