JPC-2997, a New Aminomethylphenol with High
            <i>In Vitro</i>
            and
            <i>In Vivo</i>
            Antimalarial Activities against Blood Stages of Plasmodium

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

doi:10.1128/aac.03762-14

Cited by 16 publications

(11 citation statements)

References 35 publications

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“…In addition to developing fast-acting nonartemisinin derivatives, newer longer-acting partner drugs are urgently required. We recently reported on the preclinical development of a 2-aminomethylphenol antimalarial compound, JPC-2997 (11), that resulted from comprehensive structure-activity relationship (SAR) studies of this class of molecule. These SAR studies have subsequently identified a superior trifluoromethyl pyridine analog of 2-aminomethylphenol, JPC-3210 (12), with improved in vitro and in vivo activity and a longer elimination half-life in mice (13).…”

mentioning

confidence: 99%

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

Birrell¹,

Heffernan

Schiehser

et al. 2018

Antimicrob Agents Chemother

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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.

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mentioning

confidence: 99%

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

Birrell¹,

Heffernan

Schiehser

et al. 2018

Antimicrob Agents Chemother

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show abstract

“…Previously, we reported on the pharmacokinetic properties of JPC-2997 in mice, revealing that the drug is widely distributed to tissues, with a low plasma clearance and a lengthy elimination half-life (6). In the present study, we determined the pharmacokinetics of JPC-2997, JPC-3186, and JPC-3210 in healthy ARC female mice (aged 6 to 7 weeks; mean Ϯ standard deviation [SD] body weight, 28.0 Ϯ 3.2 g; Animal Resources Centre, Perth, Australia).…”

mentioning

confidence: 99%

Lead Selection of a New Aminomethylphenol, JPC-3210, for Malaria Treatment and Prevention

Chavchich¹,

Birrell²,

Ager

et al. 2016

Antimicrob Agents Chemother

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“…When the parasite density reached 3.85% (188,771 parasites/lL), 2 mL of blood was obtained to prepare wild-type and TF-A treated parasite inocula. The monkey was then treated with oral artesunate (10 mg/ kg) daily for 2 days followed on the third day with a single oral dose of the aminomethylphenol, JPC-2997, at 20 mg/kg (Birrell et al, 2015). Following drug treatment, the donor monkey was referred to as infected and drug-cured monkey 1 (IDC1).…”

Section: Immunisation and Challenge Protocolmentioning

confidence: 99%

Persistence and immunogenicity of chemically attenuated blood stage Plasmodium falciparum in Aotus monkeys

Stanisic

Breda³

et al. 2016

International Journal for Parasitology

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JPC-2997, a New Aminomethylphenol with High In Vitro and In Vivo Antimalarial Activities against Blood Stages of Plasmodium

Cited by 16 publications

References 35 publications

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

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

Lead Selection of a New Aminomethylphenol, JPC-3210, for Malaria Treatment and Prevention

Persistence and immunogenicity of chemically attenuated blood stage Plasmodium falciparum in Aotus monkeys

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