Hypochlorous acid, a major oxidant produced by activated neutrophils, has low effect on two pyridobenzazepine derivatives, JL 3 and JL 13

JL 13 (5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b]-[1,5]benzoxazepine fumarate) and JL 3 (10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1,4]benzothia zepine), two pyridobenzazepine derivatives structurally related to clozapin e, were selected for further development. Due to their structural similarit y to clozapine, they are haunted by the spectre of clozapine-induced agranu locytosis. In a previous study, JL 13 was shown to be less sensitive to oxi dation than clozapine. In the present paper. using an in vitro procedure, w e report the effect of hypochlorous acid (HOCl), a major in vivo oxidant, o n both drugs. It appears that the oxidations of JL 3 and JL 13, unlike cloz apine, are very slow and little secondary product is formed. Moreover, in c ontrast to clozapine, the products that were formed are not reactive and th us do not react with glutathione or N-acetylcysteine, Thus, if, as postulat ed for clozapine, drug-induced agranulocytosis is due to a reactive metabol ite formed by neutrophils or their precursors, JL 3 and JL 13 would not be expected to cause the same adverse reaction.