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

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

  • ACS Omega. 2022 Mar 30;7(14):12401-12411. doi: 10.1021/acsomega.2c01099.
Yuxiang Dong 1,  Yogesh Sonawane 1,  Steven P Maher 2,  Anne-Marie Zeeman 3,  Victor Chaumeau 4 5,  Amélie Vantaux 6,  Caitlin A Cooper 2,  Francis C K Chiu 7,  Eileen Ryan 7,  Jenna McLaren 7,  Gong Chen 7,  Sergio Wittlin 8,  Benoît Witkowski 6,  François Nosten 4 5,  Kamaraj Sriraghavan 1,  Dennis E Kyle 2,  Clemens H M Kocken 3,  Susan A Charman 7,  Jonathan L Vennerstrom 1
Affiliations

Affiliations

  • 1 College of Pharmacy, University of Nebraska Medical Center, 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
  • 2 Center for Tropical and Emerging Global Diseases, University of Georgia, 370 Coverdell Center, 500 D.W. Brooks Drive, Athens, Georgia 30602, United States.
  • 3 Department of Parasitology, Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands.
  • 4 Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 68/30 Bantung Road, Mae Sot, Tak 63110, Thailand.
  • 5 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research building, University of Oxford Old Road Campus, Oxford OX3 7DQ, U.K.
  • 6 Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, 5 Boulevard Monivong, P.O. Box 983, Phnom Penh 120 210, Cambodia.
  • 7 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • 8 Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland.
PMID: 35449901 DOI: 10.1021/acsomega.2c01099
Abstract

The catechol derivative RC-12 (WR 27653) (1) is one of the few non-8-aminoquinolines with good activity against hypnozoites in the gold-standard Plasmodium cynomolgi-rhesus monkey (Macaca mulatta) model, but in a small clinical trial, it had no efficacy against Plasmodium vivax hypnozoites. In an attempt to better understand the pharmacokinetic and pharmacodynamic profile of 1 and to identify potential active metabolites, we now describe the phase I metabolism, rat pharmacokinetics, and in vitro liver-stage activity of 1 and its metabolites. Compound 1 had a distinct metabolic profile in human vs monkey liver microsomes, and the data suggested that the O-desmethyl, combined O-desmethyl/N-desethyl, and N,N-didesethyl metabolites (or a combination thereof) could potentially account for the superior liver stage antimalarial efficacy of 1 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 O-desmethyl/N-desethyl metabolite, which was the only metabolite tested that had any activity against liver-stage P. vivax; however, it was not consistently active against liver-stage P. cynomolgi. As 1 and all but one of its identified Phase I metabolites had no in vitro activity against P. vivax or P. cynomolgi liver-stage malaria parasites, we suggest that there may be additional unidentified active metabolites of 1 or that the exposure of 1 achieved in the reported unsuccessful clinical trial of this drug candidate was insufficient to kill the P. vivax hypnozoites.

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