Artefenomel Regioisomer RLA-3107 Is a Promising Lead for the Discovery of Next-Generation Endoperoxide Antimalarials

Brian R Blank; Jiri Gut; Philip J Rosenthal; Adam R Renslo

doi:10.1021/acsmedchemlett.3c00039

Artefenomel Regioisomer RLA-3107 Is a Promising Lead for the Discovery of Next-Generation Endoperoxide Antimalarials

ACS Med Chem Lett. 2023 Apr 4;14(4):493-498. doi: 10.1021/acsmedchemlett.3c00039. eCollection 2023 Apr 13.

Authors

Brian R Blank¹, Jiri Gut², Philip J Rosenthal², Adam R Renslo¹

Affiliations

¹ Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States.
² Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California 94143, 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.