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

Chavchich, Marina; Birrell, Geoff W.; Ager, Arba L.; Mackenzie, Donna; Heffernan, Gavin D.; Schiehser, Guy A.; Jacobus, Laura R.; Shanks, G. Dennis; Jacobus, David P.; Edstein, Michael D.

doi:10.1128/aac.03066-15

Cited by 20 publications

(17 citation statements)

References 18 publications

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“…In the present study, the mean Ϯ standard deviation (SD) parasitemia was 6.9% Ϯ 2.2% before treatment. As previously reported, JPC-3210 is not a rapidly acting antimalarial drug (13). By day 4 posttreatment, 4 of 5 mice were still parasitemic, but by day 5, all mice were blood film negative after the single oral dose of 80 mg/kg of JPC-3210, with no recurrence of malaria over a 28-day follow-up period.…”

Section: Resultssupporting

confidence: 70%

“…Blood and plasma concentrations of JPC-3210 were measured by LC-MS/MS. The lower limit of quantification of JPC-3210 was 0.5 ng/ml in both blood and plasma, with an inaccuracy of Ͻ7.8%, using 50 l of sample, as previously described (13), with the modification that JPC-3302 (m/z 410.3/337.4) was used as the internal standard. The interassay precision of the analysis (percent coefficient of variation [CV]) for JPC-3210 in blood over the concentration range of 0.5 ng/ml to 1,000 ng/ml was Ͻ7.4% (n ϭ 10), and that in plasma over the concentration range of 0.5 ng/ml to 2,000 ng/ml was Ͻ6.6% (n ϭ 10).…”

Section: Drugs 4-(tert-butylmentioning

confidence: 99%

“…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). Thus, JPC-3210 has replaced JPC-2997 as the lead compound and is currently in preclinical development by the Medicines for Malaria Venture (MMV) and given the number MMV892646.…”

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confidence: 99%

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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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Section: Resultssupporting

confidence: 70%

Section: Drugs 4-(tert-butylmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Three laboratory-adapted P. falciparum lines were used in this study: D6 from Sierra Leone is chloroquine and pyrimethamine sensitive but innately less susceptible to mefloquine, MRA1239 is DHA sensitive but chloroquine and mefloquine resistant, and MRA1240 is DHA, chloroquine, and mefloquine resistant. 19 Both MRA139 and MRA1240 are recent lines from Cambodia and were obtained from BEI Resources (Manassas, VA).…”

Section: Methodsmentioning

confidence: 99%

Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate–Amodiaquine and Artemisinin–Piperaquine in Healthy Volunteers for Preselection Malaria Therapy

Quang

Chavchich²,

Anh

et al. 2018

The American Journal of Tropical Medicine and Hygiene

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The pharmacokinetics (PK) and ex vivo activity (pharmacodynamics [PD]) of two artemisinin combination therapies (ACTs) (artemisinin-piperaquine [ARN-PPQ] [Artequick] and artesunate-amodiaquine [ARS-AQ] [Coarsucam]) in healthy Vietnamese volunteers were compared following 3-day courses of the ACTs for the preselection of the drugs for falciparum malaria therapy. For PK analysis, serial plasma samples were collected from two separate groups of 22 volunteers after ACT administration. Of these volunteers, ex vivo activity was assessed in plasma samples from seven volunteers who received both ACTs. The area under the concentration-time curve (AUC) was 3.6-fold higher for dihydroartemisinin (active metabolite of ARS) than that for ARN, whereas the AUC of desethylamodiaquine (active metabolite of AQ) was 2.0-fold lower than that of PPQ. Based on the 50% inhibitory dilution values of the volunteers' plasma samples collected from 0.25 to 3 hours after the last dose, the ex vivo activity of ARS-AQ was 2.9- to 16.2-fold more potent than that of ARN-PPQ against the drug-sensitive D6 line. In addition, at 1.5, 4.0, and 24 hours after the last dose, the ex vivo activity of ARS-AQ was 20.8-, 3.5-, and 8.5-fold more potent than that of ARN-PPQ against the ARN-sensitive MRA1239 line. By contrast, at 1.5 hours, the ex vivo activity of ARS-AQ was 5.4-fold more active than that of ARN-PPQ but had similar activities at 4 and 24 hours against the ARN-resistant MRA1240 line. The PK-PD data suggest that ARS-AQ possesses superior antimalarial activity than that of ARN-PPQ and would be the preferred ACT for further in vivo efficacy testing in multidrug-resistant falciparum malaria areas.

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“…Some representative pharmacologically important drugs incorporating aminomethylphenol skeleton are WR-194,965, JPC-2997, MK-4815, JPC-3186 and JPC-3210 ( Figure 1). 7,8 Notably, a class of 2aminomethylphenol displays saluretic profiles and can be used in the treatment of hypertension or edematous disorders. 9 In addition, aminomethylphenol figure presents a key structural motif to prepare human hair dye coupler compounds, 10 heat curable thermosetting surface coating, 11 corrosion inhibiting coating to a metal surface, 12 and as additives for lubricating oils.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of aminomethylphenol derivatives via magnetic nano $$\hbox {Fe}_{3}\hbox {O}_{4}$$ Fe 3 O 4 catalyzed one pot Peta

Chacko

Shivashankar

2018

J Chem Sci

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A novel library of aminomethylphenol has been developed using magnetic Fe 3 O 4 nanoparticles via Petasis borono-Mannich reaction of salicylaldehydes, secondary amines and phenyl boronic acids. This one-pot protocol features mild reaction conditions, excellent yields in short reaction times, readily available starting materials, good functional group tolerance and reusability of the catalyst for four consecutive cycles without significant loss in its activity.

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

Cited by 20 publications

References 18 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

Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate–Amodiaquine and Artemisinin–Piperaquine in Healthy Volunteers for Preselection Malaria Therapy

Synthesis of aminomethylphenol derivatives via magnetic nano $$\hbox {Fe}_{3}\hbox {O}_{4}$$ Fe 3 O 4 catalyzed one pot Peta

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