Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria

Lisa Frueh, Yuexin Li, Michael W. Mather, Qigui Li, Sovitj Pou, Aaron Nilsen, Rolf W. Winter, Isaac P. Forquer, April M. Pershing, Lisa H. Xie, Martin J. Smilkstein, Diana Caridha, Dennis R. Koop, Robert F. Campbell, Richard J. Sciotti, Mara Kreishman-Deitrick, Jane X. Kelly, Brian Vesely, Akhil B. Vaidya, Michael K. Riscoe

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

ELQ-300 is a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum. While ELQ-300 is highly effective when administered in a low multidose regimen, poor aqueous solubility and high crystallinity have hindered its clinical development. To overcome its challenging physiochemical properties, a number of bioreversible alkoxycarbonate ester prodrugs of ELQ-300 were synthesized. These bioreversible prodrugs are converted to ELQ-300 by host and parasite esterase action in the liver and bloodstream of the host. One such alkoxycarbonate prodrug, ELQ-331, is curative against Plasmodium yoelii with a single low dose of 3 mg/kg in a murine model of patent malaria infection. ELQ-331 is at least as fully protective as ELQ-300 in a murine malaria prophylaxis model when delivered 24 h before sporozoite inoculation at an oral dose of 1 mg/kg. Here, we show that ELQ-331 is a promising prodrug of ELQ-300 with improved physiochemical and metabolic properties and excellent potential for clinical formulation.

Original languageEnglish (US)
Pages (from-to)728-735
Number of pages8
JournalACS Infectious Diseases
Volume3
Issue number10
DOIs
StatePublished - Oct 13 2017

Keywords

  • Plasmodium falciparum
  • cytochrome bc1
  • malaria
  • prodrug

ASJC Scopus subject areas

  • Infectious Diseases

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    Frueh, L., Li, Y., Mather, M. W., Li, Q., Pou, S., Nilsen, A., Winter, R. W., Forquer, I. P., Pershing, A. M., Xie, L. H., Smilkstein, M. J., Caridha, D., Koop, D. R., Campbell, R. F., Sciotti, R. J., Kreishman-Deitrick, M., Kelly, J. X., Vesely, B., Vaidya, A. B., & Riscoe, M. K. (2017). Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria. ACS Infectious Diseases, 3(10), 728-735. https://doi.org/10.1021/acsinfecdis.7b00062