Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, Florida 33620, United States.
Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, 102 Hurtig Hall, Boston, Massachusetts 02115, United States.
J Med Chem. 2021 May 27;64(10):6581-6595. doi: 10.1021/acs.jmedchem.0c01104. Epub 2021 May 12.
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)-quinolones, which entered and failed preclinical development over the last decade. With the amino AOCOM ether prodrug moiety, the 3-aryl-4(1)-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.
由于许多小分子的水溶性差、吸收有限和口服生物利用度低，它们的临床前和临床开发受到了阻碍。在此，我们披露了一种通用的前药方法，将有前途的先导化合物转化为氨基烷氧基羰氧基甲基（氨基 AOCOM）醚取代的类似物，这些类似物显示出显著提高的水溶性和增强的口服生物利用度，恢复了典型候选药物特征的关键要求。该前药完全独立于生物转化和动物，因为它通过 pH 触发的分子内环化-消除反应转化为活性化合物。作为概念验证，该新型氨基 AOCOM 醚前药方法在过去十年中进入并未能进行临床前开发的各种抗疟 4(1)-喹诺酮类抗疟化合物系列上得到了验证。带有氨基 AOCOM 醚前药部分，3-芳基-4(1)-喹诺酮类临床前候选药物在 3mg/kg 的口服剂量下，在啮齿动物疟疾模型中提供了单次剂量治愈，而无需使用先进的制剂技术。
