Altomare C, Cellamare S, Summo L, Catto M, Carotti A, Thull U, Carrupt P A, Testa B, Stoeckli-Evans H
Institut de Chimie, Faculté de Sciences, Université de Neuchâtel, Avenue de Bellevaux 51, CH-2000 Neuchâtel, Switzerland.
J Med Chem. 1998 Sep 24;41(20):3812-20. doi: 10.1021/jm981005y.
A number of condensed pyridazines and pyrimidines were synthesized and tested for their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. Their lipophilicity was examined by measuring partition coefficients and RP-HPLC capacity factors, revealing some peculiar electronic and conformational effects. Further insights were obtained by X-ray crystallography and a thermodynamic study of RP-HPLC retention. Structure-activity relations highlighted the main factors determining both selectivity and inhibitory potency. Thus, while most of the condensed pyridazines were reversible inhibitors of MAO-B with little or no MAO-A effects, the pyrimidine derivatives proved to be reversible and selective MAO-A inhibitors. Substituents on the diazine nucleus modulated enzyme inhibition. A QSAR analysis of X-substituted 3-X-phenyl-5H-indeno[1,2-c]pyridazin-5-ones showed lipophilicity to increase MAO-B and not MAO-A inhibitory activity.
合成了多种稠合哒嗪和嘧啶，并测试了它们对单胺氧化酶-A（MAO-A）和单胺氧化酶-B（MAO-B）的抑制活性。通过测量分配系数和反相高效液相色谱容量因子来考察它们的亲脂性，揭示了一些特殊的电子和构象效应。通过X射线晶体学和反相高效液相色谱保留的热力学研究获得了进一步的见解。构效关系突出了决定选择性和抑制效力的主要因素。因此，虽然大多数稠合哒嗪是MAO-B的可逆抑制剂，对MAO-A几乎没有影响，但嘧啶衍生物被证明是可逆的选择性MAO-A抑制剂。二嗪核上的取代基调节酶抑制作用。对X-取代的3-X-苯基-5H-茚并[1,2-c]哒嗪-5-酮的定量构效关系分析表明，亲脂性增加了MAO-B而非MAO-A的抑制活性。
