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首页> 外文期刊>Journal of Medicinal Chemistry >Design, synthesis, and pharmacological evaluation of R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminocarbonylamino)-2H-1-benzopyrans: Toward tissue-selective pancreatic beta-cell K-ATP channel openers structurally related to (+/-)-cromakalim
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Design, synthesis, and pharmacological evaluation of R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminocarbonylamino)-2H-1-benzopyrans: Toward tissue-selective pancreatic beta-cell K-ATP channel openers structurally related to (+/-)-cromakalim

机译：R / S-3,4-二氢-2,2-二甲基-6-卤代-4-（苯基氨基羰基氨基）-2H-1-苯并吡喃的设计，合成和药理学评估：向组织选择性胰腺β细胞K-与（+/-）-cromakalim结构相关的ATP通道开放剂

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摘要

In the search of a novel series of benzopyrans structurally related to (+)-cromakalim and acting as pancreatic beta-cell potassium channel openers, several R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminocarbonyl-amino)-2H-1-benzopyrans with or without a substituent on the phenyl ring in the 4-position were synthesized. Their activity on rat-insulin-secreting cells and rat aorta rings was compared to that of the KATP channel activators (+)-cromakalim, diazoxide, (+)-pinacidil, and compound 4. Structure-activity relationships indicated that the most pronounced inhibitory activity on the pancreatic tissue was obtained by introducing a meta- or para-electron-withdrawing group (a chlorine atom) on the C-4 phenyl ring (drugs 37-42). Such molecules, unlike the parent compound (+)-cromakalim, also exhibited a high selectivity for the pancreatic tissue versus the vascular tissue. Radioisotopic and electrophysiological investigations performed with R/S6-chloro-4-(3-chlorophenylaminocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (38) confirmed that the drug activated pancreatic KATP channels.
机译：在寻找一系列与（+）-cromakalim结构相关并充当胰腺β细胞钾通道开放剂的苯并吡喃类化合物时，一些R / S-3,4-dihydro-2,2-methyldimethyl-6-halo-4合成了在4-位的苯环上具有或没有取代基的-（苯基氨基羰基-氨基）-2H-1-苯并吡喃。将它们对大鼠胰岛素分泌细胞和大鼠主动脉环的活性与KATP通道激活剂（+）-克罗卡林，二氮嗪，（+）-吡那地尔和化合物4的活性进行了比较。结构-活性关系表明，抑制作用最明显通过在C-4苯环上引入间位或对位电子吸收基团（氯原子）（药物37-42），可获得对胰腺组织的活性。与母体化合物（+）-cromakalim不同，此类分子对胰腺组织和血管组织也显示出高选择性。用R / S6-氯-4-（3-氯苯基氨基羰基氨基）-3,4-二氢-2,2-二甲基-2H-1-苯并吡喃进行的放射性同位素和电生理研究（38）证实了该药物激活了胰腺KATP通道。

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