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

1999; Elsevier BV; Volume: 34; Issue: 9 Linguagem: Inglês

10.1016/s0223-5234(99)00220-2

1768-3254

Mats Linderberg,

Peroxisome Proliferator-Activated Receptors

Novel 4,5-, 4,6-disubstituted and 4,5,6-trisubstituted 3-hydroxyanthranilic acid derivatives were synthesized and their ability to reduce the production of the excitotoxin quinolinic acid (QUIN) by inhibition of brain 3-hydroxyanthranilic acid dioxygenase (3-HAO) was subsequently investigated. The potency of the compounds to inhibit 3-HAO was assayed in rat brain homogenate, while chemical stability of certain compounds was studied by HPLC. The data were used to generate quantitative structure-activity relationship (QSAR) models for potency of 3-HAO inhibition and compound stability. Compounds 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 that showed high potency in vitro were also found to be efficacious inhibitors in vivo after cerebral administration in rats.