Synthesis and SAR of 4-Aryl-2-hydroxy-4-oxobut-2-enoic Acids and Esters and 2-Amino-4-aryl-4-oxobut-2-enoic Acids and Esters:  Potent Inhibitors of Kynurenine-3-hydroxylase as Potential Neuroprotective Agents

The synthesis and structure−activity relationship of a series of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids and esters and 2-amino-4-aryl-4-oxobut-2-enoic acids and esters as potent inhibitors of kynurenine-3-hydroxylase are described. These compounds are the most potent inhibitors of the kynurenine-3-hydroxylase enzyme so far disclosed. Additionally methyl 4-(3-chlorophenyl)-2-hydroxy-4-oxobut-2-enoate <BO>(2d)</BO>, 4-(3-chlorophenyl)-2-hydroxy-4-oxobut-2-enoic acid <BO>(3d)</BO>, methyl 4-(3-fluorophenyl)-2-hydroxy-4-oxobut-2-enoate <BO>(2f),</BO> and 4-(3-fluorophenyl)-2-hydroxy-4-oxobut-2-enoic acid <BO>(3f)</BO> prevent the increase in the interferon-γ-induced synthesis of quinolinic acid in primary cultures of cultured human peripheral blood monocyte-derived macrophages.