Synthesis of a highly water-soluble acacetin prodrug for treating experimental atrial fibrillation in beagle dogs.
Synthesis of a highly water-soluble acacetin prodrug for treating experimental atrial fibrillation in beagle dogs.
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DOI：
10.1038/srep25743
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发表时间：
2016-05-10
影响因子：
4.6
通讯作者：
Li GR
中科院分区：
文献类型：
--
作者：
Liu H;Wang YJ;Yang L;Zhou M;Jin MW;Xiao GS;Wang Y;Sun HY;Li GR
我们以前报道过，十二指肠给药的天然黄酮金合欢素可以有效地防止实验性房颤（AF）在犬的诱导，但是，它可能不会被用于终止AF静脉注射，由于其水溶性差。本研究旨在设计一种水溶性的金合欢素前体药物，并研究其在Beagle犬体内的抗AF作用。通过三步程序合成金合欢素前药。采用不同方法测定了金合欢素前体药物的水溶性、生物转化率和抗房颤疗效。我们的结果表明，合成的金合欢素前药的磷酸钠盐在水和临床可接受的溶液（5%葡萄糖或0.9%NaCl）中的水溶解度显著增加。在离体大鼠血浆和肝微粒体中，以及在体内比格犬中，金合欢素前体药物有效地转化为金合欢素。静脉输注金合欢素前体药物（3、6和12 mg/kg）可终止Beagle犬实验性AF，而不增加ECG QTc间期。小鼠静脉注射金合欢素前体药物的LD_（50）为721 mg/kg。我们的临床前研究表明，合成的金合欢素前药是高度水溶性和安全的，它有效地终止实验性AF在比格犬，因此可能是一个有前途的候选药物的临床试验，以治疗急性AF患者。
We previously reported that duodenal administration of the natural flavone acacetin can effectively prevent the induction of experimental atrial fibrillation (AF) in canines; however, it may not be used intravenously to terminate AF due to its poor water-solubility. The present study was to design a water-soluble prodrug of acacetin and investigate its anti-AF effect in beagle dogs. Acacetin prodrug was synthesized by a three-step procedure. Aqueous solubility, bioconversion and anti-AF efficacy of acacetin prodrug were determined with different methodologies. Our results demonstrated that the synthesized phosphate sodium salt of acacetin prodrug had a remarkable increase of aqueous solubility in H2O and clinically acceptable solution (5% glucose or 0.9% NaCl). The acacetin prodrug was effectively converted into acacetin in ex vivo rat plasma and liver microsome, and in vivo beagle dogs. Intravenous infusion of acacetin prodrug (3, 6 and 12 mg/kg) terminated experimental AF without increasing ECG QTc interval in beagle dogs. The intravenous LD50 of acacetin prodrug was 721 mg/kg in mice. Our preclinical study indicates that the synthesized acacetin prodrug is highly water-soluble and safe; it effectively terminates experimental AF in beagle dogs and therefore may be a promising drug candidate for clinical trial to treat patients with acute AF.