Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 10, Pages 6581-6595Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01104
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Funding
- Medicines for Malaria Venture [08/0068]
- National Institutes of Health [R01 GM097118, AI144464]
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The prodrug approach of converting lead compounds into amino AOCOM ether-substituted analogues improves aqueous solubility and oral bioavailability, meeting key requirements typical for drug candidate profiles. The prodrug is activated through a pH-triggered intramolecular cyclization-elimination reaction, independent of biotransformations and animal-assisted processes. This novel approach was successfully demonstrated on antimalarial compounds, achieving single-dose cures in a rodent malaria model without advanced formulation techniques.
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.
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