%0 Journal Article
%T 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.
%A Monastyrskyi A
%A Brockmeyer F
%A LaCrue AN
%A Zhao Y
%A Maher SP
%A Maignan JR
%A Padin-Irizarry V
%A Sakhno YI
%A Parvatkar PT
%A Asakawa AH
%A Huang L
%A Casandra D
%A Mashkouri S
%A Kyle DE
%A Manetsch R
%J J Med Chem
%V 64
%N 10
%D 05 2021 27
%M 33979164
%F 8.039
%R 10.1021/acs.jmedchem.0c01104
%X 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(1H)-quinolones, which entered and failed preclinical development over the last decade. With the amino AOCOM ether prodrug moiety, the 3-aryl-4(1H)-quinolone preclinical candidate was shown to provide single-dose cures in a rodent malaria model at an oral dose of 3 mg/kg, without the use of an advanced formulation technique.