Characterization of the Preclinical Pharmacology of the New 2-Aminomethylphenol, JPC-3210, for Malaria Treatment and Prevention

Abstract

The new 2-aminomethylphenol, JPC-3210, has potent antimalarial activity against multidrug-resistant lines, low cytotoxicity, and high efficacy against murine malaria. Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and the results of 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-to-plasma 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 -infected mice than in healthy mice. 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. 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 potency have led the Medicines for Malaria Venture to select JPC-3210 (MMV892646) for further advanced preclinical development.

In Vivo Efficacy and Pharmacokinetics of the 2-Aminomethylphenol Antimalarial JPC-3210 in the Aotus Monkey-Human Malaria Model

“…In the same monkeys, the blood elimination half-life of JPC-3210 was long, averaging 20.9 days for the two doses of JPC-3210. This lengthy half-life is in accord with JPC-3210 having a long blood elimination half-life in mice of 4 to 5 days and in cynomolgus macaque monkeys of approximately 12 days (15). There were no significant differences in the pharmacokinetic parameters of JPC-3210 in monkeys infected with the FVO and AMRU1 strains treated with 10 mg/kg of JPC-3210.…”

“…Hydroxylation has been identified as a major route of JPC-3210 metabolism, with at least 7% of JPC-3210 converted in monkey hepatocytes (15). The stable hydroxylated metabolite of JPC-3210 is JPC-3545, which possesses approximately 12-fold less in vitro antimalarial activity than its parent compound against the artemisinin-sensitive MRA1239 and artemisinin-resistant MRA1240 P. falciparum lines (Table S2).…”

Malaria: Introductory Concepts, Resistance Issues and Current Medicines

“…Triaminopyrimidine MMV253 (identified by AstraZeneca in 2015) and an aminomethylphenol JPC-3210 (active against multidrug resistant falciparum in vitro) are long-acting blood schizonticidal agents present in early preclinical experiments [121,122]. MMV253 (previously AZ13721412) has shown good in vitro potency and in vivo efficacy.…”

Drugs in Development for Malaria

“…MMV 253 (previously AZ13721412) is a very long-acting Plasmodium ATPase inhibitor in early preclinical development, with the goal of being part of a single-dose radical cure [ 88 , 89 ]. JPC-3210 is another promising long-acting drug shown to be active against multidrug resistant P. falciparum in vitro [ 90 , 91 ].…”