Pharmacodynamics and pharmacokinetics of YM128, a GPIIb/IIIa antagonist prodrug

Abstract

We examined the biochemical properties of YM-57029 ({4-[4-(4-Carbamimidoylphenyl)-3-oxopiperazin-1-yl]piperidino}acetic acid monohydrochloride trihydrate) and the pharmacodynamics and pharmacokinetics of its prodrug, YM128 (Ethyl (Z)-(4-{4-[4-(N 2 -hydroxycarbamimidoyl)phenyl]-3-oxopiperazin-1-yl}piperidino)acetate), an orally-active glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist. YM-57029 strongly inhibited aggregation of human platelets induced by various agonists, with IC50 values ranging from 3.6 to 51 nM. YM-57029 specifically inhibited fibrinogen binding to purified GPIIb/IIIa about 1,000-fold more potently than Arg-Gly-Asp-Ser (RGDS). Moreover, YM-57029 effectively inhibited an Arg-Gly-Asp (RGD) peptide binding to platelets, suggesting that YM-57029 competed with the RGD sequence of ligand. YM-57029 or YM128 dose-dependently inhibited ex vivo platelet aggregation after iv bolus injection or oral administration to beagle dogs and cynomolgus monkeys. However, YM128 exerted more potent and prolonged inhibitory effects on platelet aggregation than YM-57029 after oral administration to cynomolgus monkeys. Furthermore, YM-57029 prolonged template bleeding time at a dose that inhibited ex vivo platelet aggregation during cumulative iv infusion to cynomolgus monkeys. Metabolic and pharmacokinetic studies showed that YM128 effectively converted into YM-57029 in liver microsomes from humans as well as dogs and monkeys, and that bioavailabilities of YM128 in dogs and monkeys were 32.3 and 22.2%, respectively. These results suggest that YM128, a prodrug of YM-57029, may be a valuable GPIIb/IIIa antagonist with good bioavailability in humans. Drug Dev.

Combined effects of a factor Xa inhibitor YM466 and a GPIIb/IIIa antagonist YM128 on thrombosis and neointima formation in mice

“…Agents YM466 (19), YM-57029 (20) and YM128 (21) were synthesized at Yamanouchi Pharmaceutical Co., Ltd (Tokyo, Japan). Adenosine diphosphate (ADP) was purchased from MC Medical (Tokyo, Japan).…”

“…The Ki values of YM466 for human factor Xa and thrombin were 1.3 nM and over 100 µM, respectively. Furthermore, we also discovered a potent GPIIb/IIIa antagonist, YM-57029 (20), and its prodrug YM128 (21). YM-57029 inhibited fibrinogen binding to GPIIb/IIIa about 1,000-fold more potently than RGDS, but had no effect on vitronectin binding to α v β 3 and α v β 5 , or fibronectin binding to α 5 β 1 (21).…”

Investigation on pharmacokinetics, tissue distribution and excretion of a novel anticancer platinum compound by inductively coupled plasma mass spectrometry after intravenous administration to rats

“…It is imperative to investigate the preclinical pharmacokinetics and pharmacodynamics of a new drug candidate under development, which enables an understanding of the disposition of drug in vivo, including its adsorption, distribution, metabolism and excretion, and an insight of the pros and cons of the drug, as to decide the favorable dosage, etc (Suzuki et al, 2002;Meibohm et al, 2002;Jin et al, 2005). We have reported the pharmacokinetic study of the compound SM54111 following intravenous (i.v.)…”