Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1
Publication/Presentation Date
5-27-2021
Abstract
Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is completely independent of biotransformations and animal-independent because it becomes an active compound via a pH-triggered intramolecular cyclization-elimination reaction. As a proof-of-concept, the utility of this novel amino AOCOM ether prodrug approach was demonstrated on an antimalarial compound series representing a variety of antimalarial 4(1
Volume
64
Issue
10
First Page
6581
Last Page
6595
ISSN
1520-4804
Published In/Presented At
Monastyrskyi, A., Brockmeyer, F., LaCrue, A. N., Zhao, Y., Maher, S. P., Maignan, J. R., Padin-Irizarry, V., Sakhno, Y. I., Parvatkar, P. T., Asakawa, A. H., Huang, L., Casandra, D., Mashkouri, S., Kyle, D. E., & Manetsch, R. (2021). Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1H)-Quinolones with Single Dose Cures. Journal of medicinal chemistry, 64(10), 6581–6595. https://doi.org/10.1021/acs.jmedchem.0c01104
Disciplines
Medicine and Health Sciences
PubMedID
33979164
Department(s)
Department of Surgery, Department of Surgery Residents, Fellows and Residents
Document Type
Article