Synthesis and Biological Evaluation of Liguzinediol Mono- and Dual Ester Prodrugs as Promising Inotropic Agents

Molecules

Jing Zhang²  Wei Li¹  Hong-Mei Wen²  Hao-Hao Zhu²  Tian-Lin Wang²  Dong Cheng²  Kun-Di Yang²  Yu-Qing Chen² 

[1] School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, Jiangsu, China;

关键词: liguzinediol;    prodrug;    physicochemical properties;    bioconversion;    pharmacokinetics;   

DOI  :  10.3390/molecules191118057

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.