Synthesis and QSAR of substituted 3-hydroxyranthranilic acid derivatives as inhibitors of 3-hydroxyanthranilic acid dioxygenase (3-HAO)

Novel 4,5-, 4,6-disubstituted and 4,5,6-trisubstituted 3- hydroxyanthranili c acid derivatives were synthesized and their ability to reduce the product ion of the excitotoxin quinolinic acid (QUIN) by inhibition of brain 3-hydr oxyanthranilic acid dioxygenase (3-HAO) was subsequently investigated. The potency of the compounds to inhibit 3-HAO was assayed in rat brain homogena te, while chemical stability of certain compounds was studied by HPLC. The data were used to generate quantitative structure-activity relationship (QS AR) models for potency of 3-HAO inhibition and compound stability. Compound s with longer half-lives were obtained when the difference between the HOMO and LUMO was increased, while electron withdrawing groups in the 4- and 5- positions increased the potency of 3-HAO inhibition. Selected compounds tha t showed high potency in vitro were also found to be efficacious inhibitors in vivo after cerebral administration in rats. (C) 1999 Editions scientifi ques et medicales Elevier SAS.