Characterization of the preclinical pharmacology of the new 2-aminomethylphenol, JPC-3210, for malaria treatment and prevention

Geoffrey W. Birrell, Gavin D. Heffernan, Guy A. Schiehser, John Anderson, Arba L Ager, Pablo Morales, Donna MacKenzie, Karin Van Breda, Marina Chavchich, Laura R. Jacobus, G. Dennis Shanks, David P. Jacobus, Michael D. Edstein

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The new 2-aminomethylphenol, JPC-3210, has potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity, and high in vivo efficacy against murine malaria. Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and the results of in vitro screening assays, including the inhibition of cytochrome P450 (CYP450) isozymes. In mice, JPC-3210 was rapidly absorbed and had an extensive tissue distribution, with a brain tissue-toplasma concentration ratio of about 5.4. JPC-3210 had a lengthy plasma elimination half-life of about 4.5 days in mice and 11.8 days in monkeys. JPC-3210 exhibited linear single-oral-dose pharmacokinetics across the dose range of 5 to 40 mg/kg of body weight with high oral bioavailability (∼86%) in mice. Systemic blood exposure of JPC-3210 was 16.6% higher in P. berghei-infected mice than in healthy mice. In vitro studies with mice and human hepatocytes revealed little metabolism and the high metabolic stability of JPC-3210. The abundance of human metabolites from oxidation and glucuronidation was 2.0% and 2.5%, respectively. CYP450 studies in human liver microsomes showed JPC-3210 to be an inhibitor of CYP2D6 and, to a lesser extent, CYP3A4 isozymes, suggesting the possibility of a metabolic drug-drug interaction with drugs that are metabolized by these isozymes. In vitro studies showed that JPC-3210 is highly protein bound to human plasma (97%). These desirable pharmacological findings of a lengthy blood elimination half-life, high oral bioavailability, and low metabolism as well as high in vivo potency have led the Medicines for Malaria Venture to select JPC-3210 (MMV892646) for further advanced preclinical development.

Original languageEnglish (US)
Article numbere01335-17
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

Fingerprint

Malaria
Pharmacology
Isoenzymes
Cytochrome P-450 Enzyme System
Biological Availability
Haplorhini
Half-Life
Pharmacokinetics
Cytochrome P-450 CYP3A
Antimalarials
Liver Microsomes
Tissue Distribution
Plasmodium falciparum
Drug Interactions
Pharmaceutical Preparations
Hepatocytes
Body Weight
In Vitro Techniques
Brain
Proteins

Keywords

  • 2-aminomethylphenol
  • Antimalarial drug discovery
  • Cytochrome P450 inhibition
  • Metabolic stability and metabolism
  • Pharmacokinetics
  • Protein binding

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Birrell, G. W., Heffernan, G. D., Schiehser, G. A., Anderson, J., Ager, A. L., Morales, P., ... Edstein, M. D. (2018). Characterization of the preclinical pharmacology of the new 2-aminomethylphenol, JPC-3210, for malaria treatment and prevention. Antimicrobial Agents and Chemotherapy, 62(4), [e01335-17]. https://doi.org/10.1128/AAC.01335-17

Characterization of the preclinical pharmacology of the new 2-aminomethylphenol, JPC-3210, for malaria treatment and prevention. / Birrell, Geoffrey W.; Heffernan, Gavin D.; Schiehser, Guy A.; Anderson, John; Ager, Arba L; Morales, Pablo; MacKenzie, Donna; Van Breda, Karin; Chavchich, Marina; Jacobus, Laura R.; Shanks, G. Dennis; Jacobus, David P.; Edstein, Michael D.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 4, e01335-17, 01.04.2018.

Research output: Contribution to journalArticle

Birrell, GW, Heffernan, GD, Schiehser, GA, Anderson, J, Ager, AL, Morales, P, MacKenzie, D, Van Breda, K, Chavchich, M, Jacobus, LR, Shanks, GD, Jacobus, DP & Edstein, MD 2018, 'Characterization of the preclinical pharmacology of the new 2-aminomethylphenol, JPC-3210, for malaria treatment and prevention', Antimicrobial Agents and Chemotherapy, vol. 62, no. 4, e01335-17. https://doi.org/10.1128/AAC.01335-17
Birrell, Geoffrey W. ; Heffernan, Gavin D. ; Schiehser, Guy A. ; Anderson, John ; Ager, Arba L ; Morales, Pablo ; MacKenzie, Donna ; Van Breda, Karin ; Chavchich, Marina ; Jacobus, Laura R. ; Shanks, G. Dennis ; Jacobus, David P. ; Edstein, Michael D. / Characterization of the preclinical pharmacology of the new 2-aminomethylphenol, JPC-3210, for malaria treatment and prevention. In: Antimicrobial Agents and Chemotherapy. 2018 ; Vol. 62, No. 4.
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