Laboratoire de Chimie Pharmaceutique, Centre Interfacultaire de Recherche du Médicament (Drug Research Center), Université de Liège, C.H.U., 1 Avenue de l'Hôpital, B-4000 Liège, Belgium.
Bioorg Med Chem. 2009 Nov 15;17(22):7723-31. doi: 10.1016/j.bmc.2009.09.041. Epub 2009 Sep 25.
The present work aimed at exploring a series of diversely 4-arylthiourea-substituted R/S-3,4-dihydro-2,2-dimethyl-6-halo-2H-1-benzopyrans structurally related to (+/-)-cromakalim. These new compounds were examined in vitro as putative potassium channel openers (PCOs) on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (relaxation of aorta ring) and their activity was compared to that of the reference K(ATP) channel activators (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and of previously reported cromakalim analogues. Structure-activity relationships indicated that the most pronounced inhibitory activity on the insulin secretory process was obtained with molecules bearing a strong meta- or para-electron-withdrawing group (CN or NO(2)) on the phenyl ring of the arylthiourea moiety at the 4-position of the benzopyran nucleus (compounds 12-23). Among those, R/S-6-chloro-4-(4-cyanophenylaminothiocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (16) was found to be the most potent benzopyran-type inhibitor of insulin release ever described. Most of these original benzopyran derivatives show increased selectivity for pancreatic versus vascular tissue. Radioisotopic investigations indicated that these new compounds activated pancreatic K(ATP) channels.
本工作旨在探索一系列结构相关的 4-芳基硫脲取代的 R/S-3,4-二氢-2,2-二甲基-6-卤-2H-1-苯并吡喃，它们是（±）-克罗卡林的类似物。这些新化合物在体外作为潜在的钾通道开放剂（PCOs）进行了测试，作用靶点为大鼠胰岛（抑制胰岛素释放）以及大鼠主动脉环（主动脉环松弛），并将其活性与参考 K（ATP）通道激活剂（±）-克罗卡林、（±）-匹那地尔、二氮嗪和以前报道的克罗卡林类似物进行了比较。构效关系表明，在苯并吡喃核的 4-位上带有强的间位或对位吸电子基团（CN 或 NO2）的芳基硫脲部分的苯环上，具有最强的胰岛素分泌过程抑制活性的分子（化合物 12-23）。在这些化合物中，R/S-6-氯-4-（4-氰基苯氨基硫代甲酰氨基）-3,4-二氢-2,2-二甲基-2H-1-苯并吡喃（16）被发现是迄今为止描述的最强的苯并吡喃类胰岛素释放抑制剂。这些新的苯并吡喃衍生物大多数对胰腺组织相对于血管组织具有更高的选择性。放射性同位素研究表明，这些新化合物激活了胰腺 K（ATP）通道。
