Synthesis, Biological Evaluation, and Pharmacokinetic Study of Novel Liguzinediol Prodrugs

Abstract

Liguzinediol (LZDO) ester prodrugs 3–5 were synthesized and evaluated in vitro and in vivo for their potential use in prolonging the half-life of the parent drug LZDO (1a) in vivo. Prodrugs 3–5 were found to display a potent positive inotropic effect on the myocardium, without the risk of arrhythmia. Prodrugs 3–5 rapidly underwent enzymatic hydrolysis to release the parent compound LZDO in 1–3 h in rat liver microsomes and rat plasma. The half-life of the parent compound was prolonged after intragastric administration of prodrug 3, which was found to be a superior prodrug candidate for increasing myocardial contractility.

A Phenolic Ester of <i>O</i>-Desmethylvenlafaxine (ODV) Improves Uptake of ODV into the Brain

“…Prodrugs are usually designed to improve intestinal absorption (Mizuno et al, 2003), increase oral bioavailability (Kahns et al, 1992) and reduce adverse effects (Bandgar et al, 2011), etc. A promising oral prodrug is expected to be stable at different pH encountered in the gastrointestinal tract and experience quick and complete transform to parent drug in whole blood or microsomes (Liu et al, 2013). In this study, with the aim of testing the stabilities of O-19 at different pH encountered in the gastrointestinal tract, the aqueous stabilities of O-19 were determined in PBS solution at pH 1.2 (the simulated gastric fluid), pH 6.8 and pH 7.4 (the simulated intestinal juice) at 25 and 37°C (Liu, 2007;Qandil et al, 2011;Redasani and Bari, 2012).…”

Pharmacokinetics, Tissue Distribution, and Druggability Prediction of the Natural Anticancer Active Compound Cytisine <i>N</i>-Isoflavones Combined with Computer Simulation

“…Therefore, it is crucial to predict the pharmacokinetic parameters of potential lead compounds early and accurately. 17,18) From the "Prodrug Design Concepts" [19][20][21] came a proposal to study pharmacokinetics in advance. The idea is to use computer-aided drug design technology to study pharmacokinetics and tissue distribution before conducting in-depth pharmacodynamic experiments.…”

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.…”