Kynureninase inhibitors

Chlorodifluoromethylketones underwent aldol reactions (Eq. 124) via zinc enolates, to afford good yields of a,a-difluoro-/ -hydroxy ketones, in a study by the Kyoto group [327]. Copper(I) or silver salt catalysis was essential and boron-trifluoride additive appeared to exert a key role in the conversion to the enolate. Earlier [328], chlorodifluoromethyl ketones had been converted to the di-fluoroenoxy silanes by the action of zinc in the presence of chlorotrimethyl silane. A difluoroenoxy silane was used by McCarthy and co-workers [329] to synthesise a kynureninase inhibitor (Eq. 125) Lewis acid-mediated reaction with a chloroglycinate installed the key carbon-carbon bond. 

Moroni F, Carpenedo R, Chiarugi A (1996) Kynurenine hydroxylase and kynureninase inhibitors as tools to study the role of kynurenine metabolites in the central nervous system. Adv Exp Med Biol 398 203-210... 

Chiarugi A, Carpenedo R, Moroni F (1996) Kynurenine disposition in blood and brain of mice Effects of selective inhibitors of kynurenine hydroxylase and of kynureninase. J Neurochem 67 692-698. 

As discussed above, inhibition of key enzymes of the KP (Fig. 1) may represent a viable opportunity to develop therapeutic agents for the treatment of a number of inflammatory, neurodegenerative, and psychiatric disorders. In this section, we will review the available chemical inhibitors of the different enzymes in the KP, with a broader focus on KMO however, we will also briefly review the current status of inhibitors of IDO, kynurenine aminotransferase II (KAT II), kynureninase, and 3-hydroxyanthranilic acid oxygenase (HAO). 

Kynureninase catalyzes the hydrolytic cleavage of both kynurenine and 3-hydro-xykynurenine to generate anthranilic acid and 3-hydroxyanthranilic acid, respectively [55]. The majority of inhibitors of kynureninase are substrate based and are designed based on the postulated transition state intermediate where water attacks the benzoyl group carbonyl through a PLP-dependant mechanism. The hydroxy (16 = 0.3 pM) and sulfone (17 IC50 =11 pM) derivatives have... 

Drysdale MJ, Reinhard JF (1998) S-aryl cysteine S, S-dioxides as inhibitors of mammalian kynureninase. Bioorg Med Chem Lett 8 133-138... 

Walsh HA, Leslie PL, O Shea KC, Botting NP (2002) 2-Amino-4[3 -ydroxyphenyl]-4-hydro-xybutanoic acid a potent inhibitor of rat and recombinant human kynureninase. Bioorg Med Chem Lett 12 361-363... 

Lima S, Kumar S, Gawandi V, Momany C, Phillips RS (2009) Crystal structure of the Homo sapiens kynureninase-3-hydroxhippuric acid inhibitor complex insights into the molecular basis of kynureninase substrate specificity. J Med Chem 52 389-396... 

Giordani A, Corti L, Cini M, Marconi M, Pillan A, Ferrario R, Schwarcz R, Guidetti P, Speciale C, Varasi M (1996) Benzoylalanine analogues as inhibitors of rat brain kynureninase and kynurenine 3-hydroxylase. Adv Exp Med Biol 398 499-505... 

---