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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria
ACS infectious diseases, v 3(10), pp 728-735
13 Oct 2017
PMID: 28927276
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria
- Creators
- Lisa Frueh - Portland VA Medical CenterYuexin Li - Portland VA Medical CenterMichael W Mather - Drexel UniversityQigui Li - Walter Reed Army Institute of ResearchSovitj Pou - Oregon Health & Science UniversityAaron Nilsen - Portland VA Medical CenterRolf W Winter - Portland VA Medical CenterIsaac P Forquer - Portland VA Medical CenterApril M Pershing - Drexel UniversityLisa H Xie - Walter Reed Army Institute of ResearchMartin J Smilkstein - Portland VA Medical CenterDiana Caridha - Walter Reed Army Institute of ResearchDennis R Koop - Oregon Health & Science UniversityRobert F Campbell - Walter Reed Army Institute of ResearchRichard J Sciotti - Walter Reed Army Institute of ResearchMara Kreishman-Deitrick - Walter Reed Army Institute of ResearchJane X Kelly - Portland VA Medical CenterBrian Vesely - Walter Reed Army Institute of ResearchAkhil B Vaidya - Drexel UniversityMichael K Riscoe - Portland VA Medical Center
- Publication Details
- ACS infectious diseases, v 3(10), pp 728-735
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; Environmental and Occupational Health
- Web of Science ID
- WOS:000413179000006
- Scopus ID
- 2-s2.0-85031497521
- Other Identifier
- 991019168046804721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Infectious Diseases