STRUCTURAL FEATURES ASSOCIATED WITH REACTIVE METABOLITE FORMATION IN CLOZAPINE ANALOGS

Clozapine is associated with a high incidence of agranulocytosis. We h ad previously found that it is oxidized by granulocytes, or simply HOC l, to a reactive metabolite that irreversibly binds to the cells, and we proposed that this reactive metabolite is responsible for clozapine -induced agranulocytosis. The reactive metabolite appeared to be a nit renium ion formed by chlorination of the nitrogen bridge between the t wo aromatic rings. If this is correct, analogs that contain this struc tural feature should also be oxidized to a reactive intermediate while those not possessing this feature would, at least, not form the same type of reactive intermediate and, therefore, may not induce agranuloc ytosis. We tested the first part of this hypothesis with three clozapi ne analogs that do contain a nitrogen bridge and three that do not. Co nsistent with the hypothesis, the three analogs that do contain the ni trogen bridge formed reactive intermediates that could be trapped with glutathione when oxidized by HOCl, myeloperoxidase or activated neutr ophils. In contrast, we found no evidence of a reactive intermediate o n oxidation of analogs that contained an oxygen or sulfur bridge rathe r than a nitrogen bridge. If such reactive metabolites are responsible for drug-induced agranulocytosis, it should be possible to use such a simple screening method to test drugs at an early stage in their deve lopment for the potential to induce agranulocytosis. (C) 1997 Elsevier Science Ireland Ltd.