Kadaba P K
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, A. B. Chandler Medical Center, University of Kentucky, Lexington 40536-0082.
J Med Chem. 1988 Jan;31(1):196-203. doi: 10.1021/jm00396a032.
Pioneering studies in our laboratories have led to the emergence of the delta 2-1,2,3-triazolines (4,5-dihydro-1H-1,2,3-triazoles) and the closely related 1H-1,2,3-triazoles as a unique family of anticonvulsant agents hitherto unknown. Unlike the traditional anticonvulsants, the dicarboximide moiety is absent from the traiazoline ring system. This paper examines the results of evaluation of several groups of 1-aryl-5-pyridyl-substituted triazolines and triazoles with particular reference to structure-activity relationships in each compound group as well as between compounds in the different groups and the 1,5-diaryl compounds. The Topliss manual approach for application fo the Hansch method is employed for the rational design of triazoline/triazole anticonvulsants. Anticonvulsant activity was determined, after intraperitoneal administration, in two standard seizure models in the mouse, the MES and scMet tests. Central nervous system toxicity was evaluated in the rotorod ataxia test. Analysis of structure-activity relationships using the Topliss scheme indicated a clear pi + sigma dependency in the 1-aryl-5-(4-pyridyl)triazolines while an adverse steric effect (Es) from 4-substitution appeared to be present in the 1-aryl-5-(3-pyridyl) compounds. A similar but strong steric effect dominated the structure-activity pattern of the 1-aryl-5-(4-pyridyl)triazoles, although a sigma dependency was more evident in the 1-aryl-5-(3-pyridyl)- and the 1,5-diaryltriazole series. No significant activity was observed among the 1-aryl-5-(2-pyridyl)triazolines, and although the respective triazoles were active, the parameter dependency was not clearly defined. Similarly, the 1,5-diaryltriazolines, as a group, showed no pronounced anticonvulsant activity. However, replacement of the 5-aryl with a pyridyl group, particularly a 4-pyridyl, led to highly enhanced anticonvulsant activity. In addition, oxidation of triazolines with no anticonvulsant activity yielded, as a rule, triazoles that were active, which could be linked to their chemistry or structural conformation. The triazolines and triazoles evince anticonvulsant activity as a class and compare very well with the prototype antiepileptic drugs--ethosuximide, phenytoin, phenobarbital, valproate--in their anticonvulsant potency and minimal neurotoxicity. They have emerged as a new generation of anticonvulsant agents that show great promise as potentially useful antiepileptic drugs.
我们实验室的开创性研究催生了δ2 - 1,2,3 - 三唑啉（4,5 - 二氢 - 1H - 1,2,3 - 三唑）以及与之密切相关的1H - 1,2,3 - 三唑，它们是迄今为止未知的一类独特的抗惊厥药物。与传统抗惊厥药不同，三唑啉环系统中不存在二羧酰亚胺部分。本文考察了几组1 - 芳基 - 5 - 吡啶基取代的三唑啉和三唑的评估结果，特别提及了每个化合物组内以及不同组化合物与1,5 - 二芳基化合物之间的构效关系。采用Topliss手册中应用Hansch方法的方式对三唑啉/三唑抗惊厥药进行合理设计。腹腔注射后，在小鼠的两种标准惊厥模型即最大电休克（MES）和皮下戊四氮（scMet）试验中测定抗惊厥活性。在旋转棒共济失调试验中评估中枢神经系统毒性。使用Topliss方案分析构效关系表明，1 - 芳基 - 5 -（4 - 吡啶基）三唑啉中存在明显的π + σ依赖性，而在1 - 芳基 - 5 -（3 - 吡啶基）化合物中，4 - 取代似乎存在不利的空间效应（Es）。类似但强烈的空间效应主导了1 - 芳基 - 5 -（4 - 吡啶基）三唑的构效模式，尽管在1 - 芳基 - 5 -（3 - 吡啶基） - 和1,5 - 二芳基三唑系列中σ依赖性更为明显。在1 - 芳基 - 5 -（2 - 吡啶基）三唑啉中未观察到显著活性，并且尽管相应的三唑有活性，但参数依赖性未明确界定。同样，作为一组的1,5 - 二芳基三唑啉没有显示出明显的抗惊厥活性。然而，用吡啶基特别是4 - 吡啶基取代5 - 芳基会导致抗惊厥活性大幅增强。此外，通常无抗惊厥活性的三唑啉氧化后会产生有活性的三唑，这可能与它们的化学性质或结构构象有关。三唑啉和三唑作为一类显示出抗惊厥活性，并且在抗惊厥效力和最小神经毒性方面与抗癫痫原型药物——乙琥胺、苯妥英、苯巴比妥、丙戊酸盐——相比非常出色。它们已成为新一代抗惊厥药物，作为潜在有用的抗癫痫药物显示出巨大的前景。
