@article{9587e1df167445b08527e39c213ce876,
title = "Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria",
abstract = "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 multidose 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 h 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.",
keywords = "Plasmodium falciparum, cytochrome bc1, malaria, prodrug",
author = "Lisa Frueh and Yuexin Li and Mather, {Michael W.} and Qigui Li and Sovitj Pou and Aaron Nilsen and Winter, {Rolf W.} and Forquer, {Isaac P.} and Pershing, {April M.} and Xie, {Lisa H.} and Smilkstein, {Martin J.} and Diana Caridha and Koop, {Dennis R.} and Campbell, {Robert F.} and Sciotti, {Richard J.} and Mara Kreishman-Deitrick and Kelly, {Jane X.} and Brian Vesely and Vaidya, {Akhil B.} and Riscoe, {Michael K.}",
note = "Funding Information: Research reported in this publication was supported by the United States National Institutes of Health under award numbers AI100569 (M.K.R.) and AI028398 (A.B.V.). This project was also supported by funds from the Veterans Affairs Merit Review Program Award number i01 BX003312 (M.K.R.). Research funds were also provided by the US Department of Defense Peer Reviewed Medical Research Program (Log #PR130649; Contract #W81XWH-14-1-0447) (M.K.R.). Additional support was provided by the Military Infectious Disease Research Program. We thank Zeng Qiang, Norma Roncal, Jing Zhang, Ping Zhang, Hsiuling Lin, and Chad Black for excellent technical and managerial contributions. Analytical support was provided by the Bioanalytical Shared Resource/Pharmacokinetics Core Facility which is part of the University Shared Resource Program at Oregon Health and Sciences University. We thank Lisa Bleyle for her assistance with the LC-MS/MS analysis. Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",
year = "2017",
month = oct,
day = "13",
doi = "10.1021/acsinfecdis.7b00062",
language = "English (US)",
volume = "3",
pages = "728--735",
journal = "ACS Infectious Diseases",
issn = "2373-8227",
publisher = "American Chemical Society",
number = "10",
}