Ross S T, Kruse L I, Ohlstein E H, Erickson R W, Ezekiel M, Flaim K E, Sawyer J L, Berkowitz B A
J Med Chem. 1987 Aug;30(8):1309-13. doi: 10.1021/jm00391a008.
The 1-benzylimidazole-2-thione moiety has been previously shown by Kruse et al. to be broadly associated with dopamine beta-hydroxylase (DBH) inhibitory activity both in vitro and in vivo in spontaneously hypertensive rats (SHR). An extension of structure-activity studies to 1-(pyridylmethyl)- and 1-(oxypyridylmethyl)imidazole-2-thiones is reported here in an attempt to exploit the pH differential that exists across the chromaffin vesicle membrane. We hypothesized that the weakly basic pyridyl compounds would diffuse into the acidic vesicles in their neutral forms where protonation and concentration would occur to enhance their in vivo effectiveness as inhibitors. To test this hypothesis, isomeric 2-, 3- and 4-(1-pyridylmethyl)imidazole-2-thiones were synthesized from the appropriate pyridinecarboxaldehydes by reductive alkylation of aminoacetaldehyde dialkyl acetal followed by imidazole-2-thione formation using acidic potassium thiocyanate. Related oxypyridyl compounds were synthesized by first preparing the appropriate aldehyde intermediate followed by conversion to the imidazole-2-thione by the same procedure. The unsubstituted pyridylmethyl compounds showed modest DBH inhibition in vitro but, consistent with a transport-mediated increase in observed potency, showed significant effects in vivo to increase the vascular ratio of dopamine to norepinephrine and to lower blood pressure.
1-苄基咪唑-2-硫酮部分先前已被克鲁斯等人证明，在体外和自发性高血压大鼠（SHR）体内均与多巴胺β-羟化酶（DBH）抑制活性广泛相关。本文报道了将构效关系研究扩展至1-(吡啶甲基)-和1-(氧基吡啶甲基)咪唑-2-硫酮，以试图利用嗜铬细胞囊泡膜两侧存在的pH差异。我们推测，弱碱性的吡啶化合物将以其中性形式扩散到酸性囊泡中，在那里发生质子化和浓缩，以增强它们作为抑制剂的体内有效性。为了验证这一假设，通过用氨基乙醛二烷基缩醛进行还原烷基化，然后使用酸性硫氰酸钾形成咪唑-2-硫酮，从适当的吡啶甲醛合成了异构体2-、3-和4-(1-吡啶甲基)咪唑-2-硫酮。相关的氧基吡啶化合物通过首先制备适当的醛中间体，然后通过相同的程序转化为咪唑-2-硫酮来合成。未取代的吡啶甲基化合物在体外显示出适度的DBH抑制作用，但与观察到的效力的转运介导增加一致，在体内显示出显著的效果，可增加多巴胺与去甲肾上腺素的血管比率并降低血压。
