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

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‐(N2‐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. Res. 55:149–161, 2002. © 2002 Wiley‐Liss, Inc.