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

Authors :
Michael K. Riscoe
Yuexin Li
Richard J. Sciotti
Brian Vesely
Aaron Nilsen
Michael W. Mather
Dennis R. Koop
Akhil B. Vaidya
Rolf W. Winter
Martin J. Smilkstein
Qigui Li
Mara Kreishman-Deitrick
Diana Caridha
Lisa Frueh
Robert F. Campbell
Sovitj Pou
Lisa H. Xie
April M. Pershing
Isaac P. Forquer
Jane X. Kelly
Source :
ACS Infectious Diseases. 3:728-735
Publication Year :
2017
Publisher :
American Chemical Society (ACS), 2017.

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 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.

Details

ISSN :
23738227
Volume :
3
Database :
OpenAIRE
Journal :
ACS Infectious Diseases
Accession number :
edsair.doi.dedup.....249b65dc64b941bff90c86f25bc6788b
Full Text :
https://doi.org/10.1021/acsinfecdis.7b00062