Metabolic, Pharmacokinetic, and Activity Profile of the Liver Stage Antimalarial (RC-12).

The catechol derivative RC-12 (WR 27653) () is one of the few non-8-aminoquinolines with good activity against hypnozoites in the gold-standard -rhesus monkey () model, but in a small clinical trial, it had no efficacy against hypnozoites. In an attempt to better understand the pharmacokinetic and pharmacodynamic profile of and to identify potential active metabolites, we now describe the phase I metabolism, rat pharmacokinetics, and liver-stage activity of and its metabolites. Compound had a distinct metabolic profile in human vs monkey liver microsomes, and the data suggested that the -desmethyl, combined -desmethyl/-desethyl, and -didesethyl metabolites (or a combination thereof) could potentially account for the superior liver stage antimalarial efficacy of in rhesus monkeys vs that seen in humans. Indeed, the rate of metabolism was considerably lower in human liver microsomes in comparison to rhesus monkey microsomes, as was the formation of the combined -desmethyl/-desethyl metabolite, which was the only metabolite tested that had any activity against liver-stage ; however, it was not consistently active against liver-stage . As and all but one of its identified Phase I metabolites had no activity against or liver-stage malaria parasites, we suggest that there may be additional unidentified active metabolites of or that the exposure of achieved in the reported unsuccessful clinical trial of this drug candidate was insufficient to kill the hypnozoites.