JPC-2997, a new aminomethylphenol with high in vitro and in vivo antimalarial activities against blood stages of Plasmodium

Geoffrey W. Birrell, Marina Chavchich, Arba L. Ager, Hong Ming Shieh, Gavin D. Heffernan, Wenyi Zhao, Peter E. Krasucki, Kurt W. Saionz, Jacek Terpinski, Guy A. Schiehser, Laura R. Jacobus, G. Dennis Shanks, David P. Jacobus, Michael D. Edstein

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-phenol (JPC-2997) is a new aminomethylphenol compound that is highly active in vitro against the chloroquine-sensitive D6, the chloroquine-resistant W2, and the multidrugresistant TM90-C2B Plasmodium falciparum lines, with 50% inhibitory concentrations (IC50s) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC50s > 35 μM) to human (HepG2 and HEK293) and rodent (BHK) cell lines than the D6 parasite line. In comparison to the chemically related WR-194,965, a drug that had advanced to clinical studies, JPC-2997 was 2-fold more active in vitro against P. falciparum lines and 3-fold less cytotoxic. The compound possesses potent in vivo suppression activity against Plasmodium berghei, with a 50% effective dose (ED50) of 0.5 mg/kg of body weight/day following oral dosing in the Peters 4-day test. The radical curative dose of JPC-2997 was remarkably low, at a total dose of 24 mg/kg, using the modified Thompson test. JPC-2997 was effective in curing three Aotus monkeys infected with a chloroquine- and pyrimethamine-resistant strain of Plasmodium vivax at a dose of 20 mg/kg daily for 3 days. At the doses administered, JPC-2997 appeared to be well tolerated in mice and monkeys. Preliminary studies of JPC-2997 in mice show linear pharmacokinetics over the range 2.5 to 40 mg/ kg, a low clearance of 0.22 liters/h/kg, a volume of distribution of 15.6 liters/kg, and an elimination half-life of 49.8 h. The high in vivo potency data and lengthy elimination half-life of JPC-2997 suggest that it is worthy of further preclinical assessment as a partner drug.

Original languageEnglish (US)
Pages (from-to)170-177
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume59
Issue number1
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Birrell, G. W., Chavchich, M., Ager, A. L., Shieh, H. M., Heffernan, G. D., Zhao, W., Krasucki, P. E., Saionz, K. W., Terpinski, J., Schiehser, G. A., Jacobus, L. R., Shanks, G. D., Jacobus, D. P., & Edstein, M. D. (2015). JPC-2997, a new aminomethylphenol with high in vitro and in vivo antimalarial activities against blood stages of Plasmodium. Antimicrobial agents and chemotherapy, 59(1), 170-177. https://doi.org/10.1128/AAC.03762-14