Rodent Malaria Models

AgerJr., A. L.

doi:10.1007/978-3-642-69251-2_8

Cited by 10 publications

(7 citation statements)

References 53 publications

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“…In the Thompson test model (26) with P. berghei infected ICR mice (Fig. S5), ELQ-300 and P4Q-391 were highly potent, with fifty percent effective doses (ED 50 ) of 0.016 and 0.27 mg/kg/day, respectively (Table S6).…”

Section: In Vivo Efficacy – Blood Stage Activitymentioning

confidence: 99%

Quinolone-3-Diarylethers: A New Class of Antimalarial Drug

Nilsen¹,

et al. 2013

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Ideally antimalarial drugs can be developed which target multiple life cycle stages, thus impacting prevention, treatment and transmission of disease. Here we introduce 4-(1H)-quinolone-3-diarylethers that are selectively potent inhibitors of the parasite’s mitochondrial cytochrome bc1 complex. These compounds are highly active against the primary human malarias (falciparum and vivax), targeting the parasite at both the liver and blood stages as well as the forms that are crucial to disease transmission: gametocytes ⇒ zygotes ⇒ ookinetes ⇒ oocysts. Chosen as the preclinical candidate, ELQ-300 has good oral bioavailability at efficacious dosages in mice, is metabolically stable, and is highly active in rodent malaria models. Given a low predicted dose in patients and a long predicted half-life, ELQ-300 offers the hope of a new molecule for the treatment, prevention and, ultimately, eradication of malaria.

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Section: In Vivo Efficacy – Blood Stage Activitymentioning

confidence: 99%

Quinolone-3-Diarylethers: A New Class of Antimalarial Drug

Nilsen¹,

et al. 2013

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“…34 Female mice (Charles River Laboratories) were infected intravenously with 50,000 P. yoelii parasitized erythrocytes from a donor animal (Kenya MR4 MRA-428) . One day after inoculation, drugs (dissolved in PEG-400, chloroquine as positive control) were administered by oral gavage once daily for 4 successive days.…”

Section: Methodsmentioning

confidence: 99%

Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria

Frueh

Mather

et al. 2017

ACS Infect. Dis.

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ELQ-300 is a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum. While ELQ-300 is highly effective when administered in a low multi-dose regimen, poor aqueous solubility and high crystallinity have hindered its clinical development. To overcome its challenging physiochemical properties, a number of bioreversible alkoxycarbonate ester prodrugs of ELQ-300 were synthesized. These bioreversible prodrugs are converted to ELQ-300 by host and parasite esterase action in the liver and bloodstream of the host. One such alkoxycarbonate prodrug, ELQ-331, is curative against Plasmodium yoelii with a single low dose of 3 mg/kg in a murine model of patent malaria infection. ELQ-331 is at least as fully protective as ELQ-300 in a murine malaria prophylaxis model when delivered 24 hours before sporozoite inoculation at an oral dose of 1 mg/kg. Here, we show that ELQ-331 is a promising prodrug of ELQ-300 with improved physiochemical and metabolic properties and excellent potential for clinical formulation.

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“…29 Mice (female, CF1, Charles River Laboratories) were infected intravenously with 2.5–5.0 × 10 5 P. yoelii (Kenya strain, MR4 MRA-428) parasitized erythrocytes from a donor animal. Drug administration commenced the day after the animals were inoculated (day 1).…”

Section: Methodsmentioning

confidence: 99%

Discovery, Synthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers

et al. 2014

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The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.

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Rodent Malaria Models

Cited by 10 publications

References 53 publications

Quinolone-3-Diarylethers: A New Class of Antimalarial Drug

Quinolone-3-Diarylethers: A New Class of Antimalarial Drug

Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria

Discovery, Synthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers

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