Role of Cyclic Tertiary Amine Bioactivation to Reactive Iminium Species: Structure Toxicity Relationship

Lucija      Peterlin Masic

doi:10.2174/138920011794520044

Abstract

Cytochrome P450-mediated bioactivation of drugs to reactive metabolites has been reported to be the first step in many adverse drug reactions. Metabolic activation of cyclic tertiary amines often generates a number of oxidative products including Ndealkylation, ring hydroxylation, α-carbonyl formation, N-oxygenation, and ring opening metabolites that can be formed through iminium ion intermediates. Therapeutic pharmaceuticals and their metabolites containing a cyclic tertiary amine structure have the potential to form iminium intermediates that are reactive toward nucleophilic macromolecules. Examples of cyclic tertiary amines that have the potential for forming reactive iminium intermediates include the piperazines, piperidines, 4-hydroxypiperidines, 4-fluoropiperidines and related compounds, pyrrolidines and N-alkyltetrahydroquinolines. Major themes explored in this review include bioactivation reactions for cyclic tertiary amines, which are responsible for the formation of iminium intermediates, together with some representative examples of drugs and guidance for discovery scientists in applying the information to minimize the bioactivation potential of cyclic amine-based compounds in drug discovery. Potential strategies to abrogate reactive iminium intermediate formation are also discussed.

Keywords: Bioactivation, cyanide, cyclic tertiary amines, glutathione, iminium ion, P450, reactive metabolite, structural alert, a-carbonyl formation, N-oxygenation, N-alkyltetrahydroquinolines