Kohn H, Sawhney K N, Bardel P, Robertson D W, Leander J D
Department of Chemistry, University of Houston, Texas 77204-5641.
J Med Chem. 1993 Oct 29;36(22):3350-60. doi: 10.1021/jm00074a016.
Earlier studies showed that (R,S)-alpha-acetamido-N-benzylacetamides (2) containing a five- and six-membered aromatic or heteroaromatic group appended at the C(alpha) site displayed outstanding activity in the maximal electroshock-induced seizure (MES) test in mice. An expanded set of C(alpha)-heteroaromatic analogues of 2 have been prepared and evaluated. The observed findings extended the structure-activity relationships previously discerned for this novel class of anticonvulsants and have validated previous trends. The alpha-furan-2-yl (4), alpha-oxazol-2-yl (18), and alpha-thiazol-2-yl (19) alpha-acetamido-N-benzylacetamides afforded excellent protection against MES-induced seizures in mice. The ED50 and PI values for these adducts rivaled those reported for phenytoin. The outstanding properties provided by 4 led to an in-depth examination of the effect of structural modification at key sites within this compound on biological activity. The pharmacological data in this series indicated that stringent steric and electronic requirements existed for maximal activity and revealed the outstanding activity of (R)-(-)-alpha-acetamido-N-(4-fluorobenzyl)-alpha-(furan-2-yl)aceta mide [(R)-30].
早期研究表明，在C(α)位点带有五元或六元芳基或杂芳基的(R,S)-α-乙酰氨基-N-苄基乙酰胺(2)在小鼠最大电休克诱发惊厥(MES)试验中表现出出色的活性。现已制备并评估了一组扩展的2的C(α)-杂芳基类似物。观察到的结果扩展了此前针对这类新型抗惊厥药所识别的构效关系，并验证了先前的趋势。α-呋喃-2-基(4)、α-恶唑-2-基(18)和α-噻唑-2-基(19)α-乙酰氨基-N-苄基乙酰胺对小鼠MES诱发的惊厥提供了出色的保护作用。这些加合物的半数有效剂量(ED50)和保护指数(PI)值与苯妥英报道的值相当。4所具有的出色特性促使人们深入研究该化合物关键位点的结构修饰对生物活性的影响。该系列中的药理学数据表明，最大活性存在严格的空间和电子要求，并揭示了(R)-(-)-α-乙酰氨基-N-(4-氟苄基)-α-(呋喃-2-基)乙酰胺[(R)-30]的出色活性。
