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
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Authors
Andrii Andrii Monastyrskyi
Fabian Brockmeyer
Alexis N LaCrue
Yingzhao Zhao
Steven P Maher
Jordany R Maignan
Vivian Padin-Irizarry
Yana I Sakhno
Prakash T Parvatkar
Ami H Asakawa
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Abstract
Preclinical and clinical development of numerous<br>small molecules is prevented by their poor aqueous solubility,<br>limited absorption, and oral bioavailability. Herein, we disclose a<br>general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueoussolubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is<br>completely independent of biotransformations and animal-<br>independent because it becomes an active compound via a pH-<br>triggered intramolecular cyclization−elimination reaction. As a<br>proof-of-concept, the utility of this novel amino AOCOM ether<br>prodrug approach was demonstrated on an antimalarial compound<br>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.