Kohn H, Sawhney K N, LeGall P, Conley J D, Robertson D W, Leander J D
Department of Chemistry, University of Houston, Texas 77204-5641.
J Med Chem. 1990 Mar;33(3):919-26. doi: 10.1021/jm00165a006.
We recently reported the potent anticonvulsant activity of (R,S)-alpha-acetamido-N-benzyl-alpha-phenylacetamide (2b). Selectively substituted derivatives of this compound have now been prepared (23 examples) and evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. In several key cases, replacement of the alpha-phenyl substituent in 2b by a relatively small, electron-rich, heteroaromatic moiety led to a substantial improvement in the anticonvulsant potency of the drug candidate. The most active compounds were (R,S)-alpha-acetamido-N-benzyl-2-furanacetamide (2g) and (R,S)-alpha-acetamido-N-benzyl-2-pyrroleacetamide (2i). After ip administration, the MES ED50 values for 2g (10.3 mg/kg) and 2i (16.1 mg/kg) compared well with phenytoin (9.50 mg/kg). Evaluation of the two individual enantiomers of 2g demonstrated that the anticonvulsant activity resided in the R stereoisomer. The low ED50 value (3.3 mg/kg) for (R)-2g contributed to the large protective index (TD50/ED50) observed for this drug candidate, which approached that of phenytoin.
我们最近报道了（R，S）-α-乙酰氨基-N-苄基-α-苯乙酰胺（2b）具有强大的抗惊厥活性。现已制备了该化合物的选择性取代衍生物（23个实例），并在小鼠的最大电休克惊厥（MES）和水平筛选（毒性）试验中进行了评估。在几个关键案例中，用相对较小的、富电子的杂芳族部分取代2b中的α-苯基取代基，使候选药物的抗惊厥效力有了显著提高。活性最高的化合物是（R，S）-α-乙酰氨基-N-苄基-2-呋喃乙酰胺（2g）和（R，S）-α-乙酰氨基-N-苄基-2-吡咯乙酰胺（2i）。腹腔注射后，2g（10.3 mg/kg）和2i（16.1 mg/kg）的MES ED50值与苯妥英（9.50 mg/kg）相当。对2g的两种对映体的评估表明，抗惊厥活性存在于R立体异构体中。（R）-2g的低ED50值（3.3 mg/kg）导致该候选药物具有较大的保护指数（TD50/ED50），接近苯妥英的保护指数。
