2-(3-pyridyl)thiazolidine-4-carboxamide derivatives. III. Synthesis of metabolites and metabolism of 2-(3-pyridyl)thiazolidine-4-carboxamides YM461 and YM264 as platelet-activating factor (PAF) receptor antagonists

The metabolism of 2-(3-pyridyl)thiazolidine-4-carboxamides YM461(4)) and YM 264(5)) was investigated, and their metabolites were compared with separate ly synthesized materials by measuring H-1-NMR spectra, mass spectra, and HP LC retention times, and evaluated for platelet activating factor (PAF) anta gonistic activity. YM461 was metabolized by two different metabolic pathway s (cleavage of the thiazolidine ring and oxidation of the benzyl position), whereas YM264 was metabolized by three metabolic pathways. The minor metab olite M7 from YM264 possessed potent PAF antagonistic activity, as strong a s YM264 and this existed as an active metabolite. From pharmacokinetics stu dies, YM264 was almost completely absorbed from the gastrointestinal tract, but readily metabolized in rats. In dogs, pharmacokinetic parameters of YM 264 were significantly improved compared to those in rats, and YM264 tended to show better pharmacokinetics than YM461 due to an extension of the half -life period.