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

Abstract

Abstract: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.

A rapid and efficient analytical method for the quantification of a novel anticholinergic compound, R‐phencynonate, by stable isotope‐dilution LC–MS/MS and its application to bioavailability and dose proportionality studies

“…Moreover, compared with fatty esters, aromatic esters have more stable physicochemical properties and lower bioconversion efficiency (Zhang et al . , ). The stability of racemic phencynonate, an aromatic ester compound, has been confirmed in several biological matrices, such as rat and human blood, plasma and urine, during sample preparation and analysis processes (Chen et al, ; Kou et al, , , ).…”

“…Ester compounds, especially fatty esters, are excellent prodrugs because they are stable in vitro at the appropriate pH, but exhibit suitable in vivo lability, owing to their ability to act as enzyme substrates (Sinkula & Yalkowsky, 1975). Moreover, compared with fatty esters, aromatic esters have more stable physicochemical properties and lower bioconversion efficiency (Zhang et al, 2014). The stability of racemic phencynonate, an aromatic ester compound, has been confirmed in several biological matrices, such as rat and human blood, plasma and urine, during sample preparation and analysis processes (Chen et al, 2015;Kou et al, 2005Kou et al, , 2007Kou et al, , 2008.…”

Predicting the Enzymatic Hydrolysis Half‐lives of New Chemicals Using Support Vector Regression Models Based on Stepwise Feature Elimination

“…The plasma/blood stability dataset in this study was collected from the publicly accessible database CHEMBL and data from the literature, including the works of Buchwald and Bodor, Massarelli et al., and additional papers published in recent years . Additional details can be found in the section Collection and Cleaning of the Datasets in the file Supplementary Materials.doc .…”

Study on Pharmacokinetics of Liguzinediol and Four Metabolites in Rats by UFLC–MS/MS

“…Ligustrazine (2,3,5,6-tetramethylpyrazine, TMP), which is an active amine alkaloid isolated from the traditional Chinese herb Ligusticum wallichii Franch, has various pharmacologic activities, such as vasodilation, antiplatelet aggregation, preventing thrombosis, increasing coronary perfusion flow, and protecting heart, and it can induce positive inotropic effect on myocardium [1][2][3][4][5][6]. However, ligustrazine presented low bioavailability and short half-life in vivo, because it could be oxidized into metabolites with high polarity and excreted easily by urine.…”