Zhang Jing, Li Wei, Wen Hong-Mei, Zhu Hao-Hao, Wang Tian-Lin, Cheng Dong, Yang Kun-Di, Chen Yu-Qing
School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, Jiangsu, China.
Molecules. 2014 Nov 5;19(11):18057-72. doi: 10.3390/molecules191118057.
The potent positive inotropic effect, together with the relatively low safety risk of liguzinediol (LZDO), relative to currently available inotropic drugs, has prompted us to intensively research and develop LZDO as a potent positive inotropic agent. In this study, to obtain LZDO alternatives for oral chronic administration, a series of long-chain fatty carboxylic mono- and dual-esters of LZDO were synthesized, and preliminarily evaluated for physicochemical properties and bioconversion. Enhanced lipophilic properties and decreased solubility of the prodrugs were observed as the side chain length increased. All esters showed conspicuous chemical stability in phosphate buffer (pH 7.4). Moreover, the enzymatic hydrolysis of esters in human plasma and human liver microsomes confirmed that the majority of esters were converted to LZDO, with release profiles that varied due to the size and structure of the side chain. In vivo pharmacokinetic studies following oral administration of monopivaloyl (M5), monodecyl (M10) and monododecyl (M12) esters demonstrated the evidently extended half-lives relative to LZDO dosed alone. In particular the monopivaloyl ester M5 exhibited an optimal pharmacokinetic profile with appropriate physiochemical characteristics.
与目前可用的强心药物相比，利谷甾醇二醇（LZDO）具有强大的正性肌力作用且安全风险相对较低，这促使我们深入研究和开发LZDO作为一种强效正性肌力药物。在本研究中，为了获得可用于口服长期给药的LZDO替代物，合成了一系列LZDO的长链脂肪酸单酯和双酯，并对其理化性质和生物转化进行了初步评估。随着侧链长度增加，前药的亲脂性增强且溶解度降低。所有酯在磷酸盐缓冲液（pH 7.4）中均表现出显著的化学稳定性。此外，酯在人血浆和人肝微粒体中的酶促水解证实，大多数酯被转化为LZDO，其释放曲线因侧链的大小和结构而异。口服单新戊酰基（M5）、单癸基（M10）和单十二烷基（M12）酯后的体内药代动力学研究表明，相对于单独给药的LZDO，半衰期明显延长。特别是单新戊酰基酯M5表现出具有适当理化特性的最佳药代动力学特征。
