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

Lisa Frueh, Yuexin Li, Michael W. Mather, Qigui Li, Sovitj Pou, Aaron Nilsen, Rolf W. Winter, Isaac P. Forquer, April M. Pershing, Lisa H. Xie, Martin J. Smilkstein, Diana Caridha, Dennis Koop, Robert F. Campbell, Richard J. Sciotti, Mara Kreishman-Deitrick, Jane X. Kelly, Brian Vesely, Akhil B. Vaidya, Michael Riscoe

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)728-735
Number of pages8
JournalACS Infectious Diseases
Volume3
Issue number10
DOIs
StatePublished - Oct 13 2017

Fingerprint

Prodrugs
Malaria
Esters
Pharmaceutical Preparations
Plasmodium yoelii
Sporozoites
Liver
Antimalarials
Esterases
Plasmodium falciparum
Solubility
6-Chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one
Parasites
Infection

Keywords

  • cytochrome bc1
  • malaria
  • Plasmodium falciparum
  • prodrug

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria. / Frueh, Lisa; Li, Yuexin; Mather, Michael W.; Li, Qigui; Pou, Sovitj; Nilsen, Aaron; Winter, Rolf W.; Forquer, Isaac P.; Pershing, April M.; Xie, Lisa H.; Smilkstein, Martin J.; Caridha, Diana; Koop, Dennis; Campbell, Robert F.; Sciotti, Richard J.; Kreishman-Deitrick, Mara; Kelly, Jane X.; Vesely, Brian; Vaidya, Akhil B.; Riscoe, Michael.

In: ACS Infectious Diseases, Vol. 3, No. 10, 13.10.2017, p. 728-735.

Research output: Contribution to journalArticle

Frueh, L, Li, Y, Mather, MW, Li, Q, Pou, S, Nilsen, A, Winter, RW, Forquer, IP, Pershing, AM, Xie, LH, Smilkstein, MJ, Caridha, D, Koop, D, Campbell, RF, Sciotti, RJ, Kreishman-Deitrick, M, Kelly, JX, Vesely, B, Vaidya, AB & Riscoe, M 2017, 'Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria', ACS Infectious Diseases, vol. 3, no. 10, pp. 728-735. https://doi.org/10.1021/acsinfecdis.7b00062
Frueh, Lisa ; Li, Yuexin ; Mather, Michael W. ; Li, Qigui ; Pou, Sovitj ; Nilsen, Aaron ; Winter, Rolf W. ; Forquer, Isaac P. ; Pershing, April M. ; Xie, Lisa H. ; Smilkstein, Martin J. ; Caridha, Diana ; Koop, Dennis ; Campbell, Robert F. ; Sciotti, Richard J. ; Kreishman-Deitrick, Mara ; Kelly, Jane X. ; Vesely, Brian ; Vaidya, Akhil B. ; Riscoe, Michael. / Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria. In: ACS Infectious Diseases. 2017 ; Vol. 3, No. 10. pp. 728-735.
@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 = "cytochrome bc1, malaria, Plasmodium falciparum, 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 Dennis Koop and Campbell, {Robert F.} and Sciotti, {Richard J.} and Mara Kreishman-Deitrick and Kelly, {Jane X.} and Brian Vesely and Vaidya, {Akhil B.} and Michael Riscoe",
year = "2017",
month = "10",
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",

}

TY - JOUR

T1 - Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria

AU - Frueh, Lisa

AU - Li, Yuexin

AU - Mather, Michael W.

AU - Li, Qigui

AU - Pou, Sovitj

AU - Nilsen, Aaron

AU - Winter, Rolf W.

AU - Forquer, Isaac P.

AU - Pershing, April M.

AU - Xie, Lisa H.

AU - Smilkstein, Martin J.

AU - Caridha, Diana

AU - Koop, Dennis

AU - Campbell, Robert F.

AU - Sciotti, Richard J.

AU - Kreishman-Deitrick, Mara

AU - Kelly, Jane X.

AU - Vesely, Brian

AU - Vaidya, Akhil B.

AU - Riscoe, Michael

PY - 2017/10/13

Y1 - 2017/10/13

N2 - 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.

AB - 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.

KW - cytochrome bc1

KW - malaria

KW - Plasmodium falciparum

KW - prodrug

UR - http://www.scopus.com/inward/record.url?scp=85031497521&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85031497521&partnerID=8YFLogxK

U2 - 10.1021/acsinfecdis.7b00062

DO - 10.1021/acsinfecdis.7b00062

M3 - Article

VL - 3

SP - 728

EP - 735

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

SN - 2373-8227

IS - 10

ER -