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]benzothiazepine), two pyridobenzazepine derivatives structurally related to clozapine, were selected for further development. Due to their structural similarity to clozapine, they are haunted by the spectre of clozapine-induced agranulocytosis. In a previous study, JL 13 was shown to be less sensitive to oxidation than clozapine. In the present paper, using an in vitro procedure, we report the effect of hypochlorous acid (HOCl), a major in vivo oxidant, on both drugs. It appears that the oxidations of JL 3 and JL 13, unlike clozapine, are very slow and little secondary product is formed. Moreover, in contrast to clozapine, the products that were formed are not reactive and thus do not react with glutathione or N-acetylcysteine. Thus, if, as postulated for clozapine, drug-induced agranulocytosis is due to a reactive metabolite formed by neutrophils or their precursors, JL 3 and JL 13 would not be expected to cause the same adverse reaction.
Liégeois
J F
JF
Laboratory of Medicinal Chemistry, University of Liège, Belgium.
Zahid
N
N
Bruhwyler
J
J
Uetrecht
J
J
D014150:Antipsychotic Agents / Q000009:adverse effects / Q000378:metabolism; D003024:Clozapine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D009504:Neutrophils / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D013841:Thiazepines / Q000378:metabolism*
D014150:Antipsychotic Agents; D016877:Oxidants; D013841:Thiazepines; C103197:10-(4-methylpiperazin-1-yl)pyrido(4,3-b)(1,4)benzothiazepine; C108260:JL 13 compound; D006997:Hypochlorous Acid; D003024:Clozapine