Suzuki T, Nagaoka H, Hara H, Takeuchi M, Saito M, Yamada T, Tomioka K, Matsumoto H, Takanuki K, Mase T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Chem Pharm Bull (Tokyo). 1999 Feb;47(2):165-70. doi: 10.1248/cpb.47.165.
The metabolism of 2-(3-pyridyl)thiazolidine-4-carboxamides YM461 and YM264 was investigated, and their metabolites were compared with separately synthesized materials by measuring 1H-NMR spectra, mass spectra, and HPLC retention times, and evaluated for platelet activating factor (PAF) antagonistic activity. YM461 was metabolized by two different metabolic pathways (cleavage of the thiazolidine ring and oxidation of the benzyl position), whereas YM264 was metabolized by three metabolic pathways. The minor metabolite M7 from YM264 possessed potent PAF antagonistic activity, as strong as YM264 and this existed as an active metabolite. From pharmacokinetics studies, YM264 was almost completely absorbed from the gastrointestinal tract, but readily metabolized in rats. In dogs, pharmacokinetic parameters of YM264 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.
对2-(3-吡啶基)噻唑烷-4-羧酰胺类化合物YM461和YM264的代谢进行了研究，并通过测量1H-NMR光谱、质谱和HPLC保留时间，将它们的代谢产物与单独合成的物质进行比较，并评估其对血小板活化因子(PAF)的拮抗活性。YM461通过两种不同的代谢途径代谢(噻唑烷环的裂解和苄基位置的氧化)，而YM264通过三种代谢途径代谢。YM264的次要代谢产物M7具有强大的PAF拮抗活性，与YM264一样强，并且作为活性代谢产物存在。从药代动力学研究来看，YM264几乎完全从胃肠道吸收，但在大鼠体内易于代谢。在犬体内，YM264的药代动力学参数与大鼠相比有显著改善，并且由于半衰期的延长，YM264的药代动力学表现往往优于YM461。
