ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria.

Autor:	Miley GP; VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA., Pou S; VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA., Winter R; VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA., Nilsen A; VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA., Li Y; VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA., Kelly JX; VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA., Stickles AM; Oregon Health & Science University, Department of Molecular Microbiology and Immunology, Portland, Oregon, USA., Mather MW; Drexel University College of Medicine, Department of Microbiology and Immunology, Philadelphia, Pennsylvania, USA., Forquer IP; VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA., Pershing AM; Drexel University College of Medicine, Department of Microbiology and Immunology, Philadelphia, Pennsylvania, USA., White K; Monash University, Centre for Drug Candidate Optimization, Parkville, Australia., Shackleford D; Monash University, Centre for Drug Candidate Optimization, Parkville, Australia., Saunders J; Monash University, Centre for Drug Candidate Optimization, Parkville, Australia., Chen G; Monash University, Centre for Drug Candidate Optimization, Parkville, Australia., Ting LM; Albert Einstein College of Medicine, Departments of Medicine, Pathology, and Microbiology and Immunology, Bronx, New York, USA., Kim K; Albert Einstein College of Medicine, Departments of Medicine, Pathology, and Microbiology and Immunology, Bronx, New York, USA., Zakharov LN; CAMCOR, University of Oregon, Eugene, Oregon, USA., Donini C; Medicines for Malaria Venture, Geneva, Switzerland., Burrows JN; Medicines for Malaria Venture, Geneva, Switzerland., Vaidya AB; Drexel University College of Medicine, Department of Microbiology and Immunology, Philadelphia, Pennsylvania, USA Akhil.Vaidya@DrexelMed.edu Susan.Charman@monash.edu riscoem@ohsu.edu., Charman SA; Monash University, Centre for Drug Candidate Optimization, Parkville, Australia Akhil.Vaidya@DrexelMed.edu Susan.Charman@monash.edu riscoem@ohsu.edu., Riscoe MK; VA Medical Center, Experimental Chemotherapy Laboratory, Portland, Oregon, USA Oregon Health & Science University, Department of Molecular Microbiology and Immunology, Portland, Oregon, USA Akhil.Vaidya@DrexelMed.edu Susan.Charman@monash.edu riscoem@ohsu.edu.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2015 Sep; Vol. 59 (9), pp. 5555-60. Date of Electronic Publication: 2015 Jun 29.
DOI:	10.1128/AAC.01183-15
Abstrakt:	ELQ-300 is a preclinical candidate that targets the liver and blood stages of Plasmodium falciparum, as well as the forms that are crucial to transmission of disease: gametocytes, zygotes, and ookinetes. A significant obstacle to the clinical development of ELQ-300 is related to its physicochemical properties. Its relatively poor aqueous solubility and high crystallinity limit absorption to the degree that only low blood concentrations can be achieved following oral dosing. While these low blood concentrations are sufficient for therapy, the levels are too low to establish an acceptable safety margin required by regulatory agencies for clinical development. One way to address the challenging physicochemical properties of ELQ-300 is through the development of prodrugs. Here, we profile ELQ-337, a bioreversible O-linked carbonate ester prodrug of the parent molecule. At the molar equivalent dose of 3 mg/kg of body weight, the delivery of ELQ-300 from ELQ-337 is enhanced by 3- to 4-fold, reaching a maximum concentration of drug in serum (C max) of 5.9 μM by 6 h after oral administration, and unlike ELQ-300 at any dose, ELQ-337 provides single-dose cures of patent malaria infections in mice at low-single-digit milligram per kilogram doses. Our findings show that the prodrug strategy represents a viable approach to overcome the physicochemical limitations of ELQ-300 to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies, as well as achieving single-dose cures. (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
Databáze:	MEDLINE
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