Wu E S, Cole T E, Davidson T A, Dailey M A, Doring K G, Fedorchuk M, Loch J T, Thomas T L, Blosser J C, Borrelli A R
Department of Organic Chemistry, Pennwalt Corporation, Rochester, New York 14623.
J Med Chem. 1989 Jan;32(1):183-92. doi: 10.1021/jm00121a034.
(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple flavonoxypropanolamines was prepared to further explore the structural requirements for the antihypertensive effect of these compounds. A structure-activity relationship of these derivatives indicates that the position of the oxypropanolamine side chain, the hydroxy group of the side chain, steric bulkiness and length of N substituents, degree of the N-substitution, phenyl group at the 2-position of the chromone nucleus, and substituents of the phenyl group or B ring of the flavone play significant roles in imparting pharmacological effects. In addition, there is a good correlation between the antihypertensive activity and depletion of myocardial norepinephrine. Of these analogues tested, the most effective one was flavodilol. Only the 8-substituted analogue 6 was found to be a beta-antagonist. Flavodilol was chosen for in-depth pharmacological, toxicological, and clinical evaluation.
（3-苯基-7-黄酮氧基）丙醇胺已被证明在自发性高血压大鼠中具有降压活性。尽管它们在结构上与经典的β-肾上腺素能阻断化合物相似，但其活性并非源于对β-肾上腺素受体的抑制。在本研究中，制备了一系列简单的黄酮氧基丙醇胺，以进一步探索这些化合物降压作用的结构要求。这些衍生物的构效关系表明，氧丙醇胺侧链的位置、侧链的羟基、N取代基的空间位阻和长度、N-取代程度、色酮核2位的苯基以及黄酮B环或苯基的取代基在赋予药理作用方面起着重要作用。此外，降压活性与心肌去甲肾上腺素的耗竭之间存在良好的相关性。在这些测试的类似物中，最有效的是黄酮洛尔。仅发现8-取代类似物6是一种β-拮抗剂。选择黄酮洛尔进行深入的药理、毒理和临床评价。
