| Literature DB >> 33979164 |
Andrii Monastyrskyi1, Fabian Brockmeyer2, Alexis N LaCrue3, Yingzhao Zhao2, Steven P Maher4, Jordany R Maignan1, Vivian Padin-Irizarry5,4, Yana I Sakhno1, Prakash T Parvatkar2, Ami H Asakawa6, Lili Huang2, Debora Casandra3, Sherwin Mashkouri3, Dennis E Kyle3,4, Roman Manetsch1,2,6.
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(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.Entities:
Mesh：
Substances：
Year: 2021 PMID： 33979164 PMCID： PMC8904075 DOI： 10.1021/acs.jmedchem.0c01104
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039