McCarthy J R, Matthews D P, Broersma R J, McDermott R D, Kastner P R, Hornsperger J M, Demeter D A, Weintraub H J, Whitten J P
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
J Med Chem. 1990 Jul;33(7):1866-73. doi: 10.1021/jm00169a006.
1-(2-Thienylalkyl)imidazole-2(3H)-thiones (5a-k) are competitive inhibitors of dopamine beta-hydroxylase (DBH) and demonstrate the utility of thiophene in the design of potent competitive inhibitors of this enzyme. The structure-activity relationships for these compounds are discussed and compared with those of 1-phenylalkyl-imidazole-2(3H)-thiones (1). With the aid of molecular modeling, an idealized active-site conformer is proposed and an explanation for the difference in activity between the phenyl (1) and thienyl (5) DBH inhibitors is presented. The difference in activity is consistent with our proposal that thiophene may not always be a bioisostere for phenyl. The inhibitor of most interest, 1-[2-(2-thienyl)ethyl]imidazole-2(3H)-thione (5g), was selected for study in the spontaneously hypertensive rat. The changes in dopamine and norepinephrine levels that resulted from oral administration of 5g correlated with the reduction of blood pressure.
1-(2-噻吩基烷基)咪唑-2(3H)-硫酮(5a - k)是多巴胺β-羟化酶(DBH)的竞争性抑制剂，表明噻吩在设计该酶的强效竞争性抑制剂方面具有实用性。讨论了这些化合物的构效关系，并与1-苯基烷基-咪唑-2(3H)-硫酮(1)的构效关系进行了比较。借助分子模拟，提出了一个理想化的活性位点构象异构体，并对苯基(1)和噻吩基(5)DBH抑制剂之间的活性差异给出了解释。活性差异与我们提出的噻吩可能并不总是苯基的生物电子等排体这一观点一致。最受关注的抑制剂1-[2-(2-噻吩基)乙基]咪唑-2(3H)-硫酮(5g)被选用于自发性高血压大鼠的研究。口服5g后多巴胺和去甲肾上腺素水平的变化与血压降低相关。
