Artefenomel Regioisomer RLA-3107 Is a Promising Lead for the Discovery of Next-Generation Endoperoxide Antimalarials
Brian R Blank1, Jiri Gut2, Philip J Rosenthal2
1Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States.
Abstract:
Clinical development of the antimalarial artefenomel was recently halted due to formulation challenges stemming from the drug's lipophilicity and low aqueous solubility. The symmetry of organic molecules is known to influence crystal packing energies and by extension solubility and dissolution rates. Here we evaluate RLA-3107, a desymmetrized, regioisomeric form of artefenomel in vitro and in vivo, finding that the regioisomer retains potent antiplasmodial activity while offering improved human microsome stability and aqueous solubility as compared to artefenomel. We also report in vivo efficacy data for artefenomel and its regioisomer across 12 different dosing regimens.
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