Abstract
The use of mefloquine (MQ) for antimalarial treatment and prophylaxis has diminished largely in response to concerns about its neurologic side effects. An analog campaign designed to maintain the efficacy of MQ while minimizing blood–brain barrier (BBB) penetration has resulted in the synthesis of a prodrug with comparable-to-superior in vivo efficacy versus mefloquine in a P. berghei mouse model while exhibiting a sixfold reduction in CNS drug levels. The prodrug, WR319670, performed poorly compared to MQ in in vitro efficacy assays, but had promising in vitro permeability in an MDCK–MDR1 cell line BBB permeability screen. Its metabolite, WR308245, exhibited high predicted BBB penetration with excellent in vitro efficacy. Both WR319670 and WR308245 cured 5/5 animals in separate in vivo efficacy studies. The in vivo efficacy of WR319670 was thought to be due to the formation of a more active metabolite, specifically WR308245. This was supported by pharmacokinetics studies in non-infected mice, which showed that both IV and oral administration of WR319670 produced essentially identical levels of WR319670 and WR308245 in both plasma and brain samples at all time points. In these studies, the levels of WR308245 in the brain were 1/4 and 1/6 that of MQ in similar IV and oral studies, respectively. These data show that the use of WR319670 as an antimalarial prodrug was able to maintain efficacy in in vivo efficacy screens, while significantly lowering overall penetration of drug and metabolites across the BBB.
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This manuscript was reviewed by the Walter Reed Army Institute of Research and the US Army Medical Research and Materiel Command, and there is no objection to its publication or dissemination. The opinions expressed herein are those of the authors and do not necessarily reflect the views or opinions of the Department of the Army and the Department of Defense. All animal experiments were conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adhere to the principles stated in the Guide for the Care and Use of Laboratory Animals (National Academy Press, 1996).
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Sousa, J.C., Milner, E., Carroll, D. et al. The use of a prodrug approach to minimize potential CNS exposure of next generation quinoline methanols while maintaining efficacy in in vivo animal models. Eur J Drug Metab Pharmacokinet 39, 231–236 (2014). https://doi.org/10.1007/s13318-013-0162-9
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DOI: https://doi.org/10.1007/s13318-013-0162-9