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.
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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DOI：
10.1021/acs.jmedchem.0c01104
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发表时间：
2021-05-27
影响因子：
7.3
通讯作者：
Manetsch R
中科院分区：
文献类型：
--
作者：
Monastyrskyi A;Brockmeyer F;LaCrue AN;Zhao Y;Maher SP;Maignan JR;Padin-Irizarry V;Sakhno YI;Parvatkar PT;Asakawa AH;Huang L;Casandra D;Mashkouri S;Kyle DE;Manetsch R
许多小分子的临床前和临床开发因其水溶性差而受阻，严重限制了吸收和口服生物利用度。在此，我们公开了一种通用的前药方法，将有希望的先导化合物转化为氨基烷氧羰基氧甲基（氨基AOCOM）醚取代类似物，显示出显着改善的水溶性和增强的口服生物利用度，恢复候选药物的典型关键要求。前药完全独立于生物转化和动物独立，因为它通过ph触发的分子内环化消除反应激活。作为概念验证，这种新型氨基AOCOM醚前药方法在一个抗疟化合物系列中得到了证明，该系列代表了各种抗疟4(1H)-喹诺酮类药物，这些化合物在过去十年中进入了临床前开发，但失败了。利用氨基AOCOM醚前药部分，3-芳基-4(1H)-喹诺酮临床前候选药物可在啮齿类疟疾模型中提供单剂量治疗，口服剂量为3mg /kg，无需使用先进的配方技术。
Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, severely limiting 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 activates 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, 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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影响因子：
7.3
作者：
Neelarapu R;Maignan JR;Lichorowic CL;Monastyrskyi A;Mutka TS;LaCrue AN;Blake LD;Casandra D;Mashkouri S;Burrows JN;Willis PA;Kyle DE;Manetsch R
通讯作者：
Manetsch R
DOI：
10.1073/pnas.1414221111
发表时间：
2014-12-16
影响因子：
11.1
作者：
Belen Jimenez-Diaz, Maria;Ebert, Daniel;Guy, R. Kiplin
通讯作者：
Guy, R. Kiplin
DOI：
10.1021/jo5023958
发表时间：
2015-03-06
期刊：
The Journal of organic chemistry
影响因子：
--
作者：
Monastyrskyi A;Namelikonda NK;Manetsch R
通讯作者：
Manetsch R
影响因子：
1.8
作者：
FALKNER, FC;TWOMEY, TM;BROWDER, IW
通讯作者：
BROWDER, IW
影响因子：
15.8
作者：
malERA Consultative Group on Vaccines
通讯作者：
malERA Consultative Group on Vaccines