新型钾通道开放剂：外消旋及旋光活性N-(6-氨基-3-吡啶基)-N'-双环烷基-N"-氰基胍衍生物的制备及药理学评价

Novel potassium-channel openers: preparation and pharmacological evaluation of racemic and optically active N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives.

作者信息

Eda M, Takemoto T, Ono S, Okada T, Kosaka K, Gohda M, Matzno S, Nakamura N, Fukaya C

机构信息

Research Division, Green Cross Corporation, Osaka, Japan.

出版信息

J Med Chem. 1994 Jun 24;37(13):1983-90. doi: 10.1021/jm00039a011.

DOI:10.1021/jm00039a011

PMID:8027980

Abstract

The previous paper reported on the synthesis and pharmacological evaluation of N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives, from among which three compounds were selected as potent potassium-channel openers. In the present study, selected compounds were tested for antagonism of potassium-induced contraction of rat aorta, hypotensive activity in normotensive rats, and diuretic activity in spontaneously hypertensive rats. This led to further evaluation of compound (+/-)-10 and selection of (+)-N-(6-amino-3-pyridyl)-N'- [(1S,2R,4R)-bicyclo- [2.2.1]hept-2-yl]-N"-cyanoguanidine ((+)-10) (AL0670) for development as an antihypertensive agent. Although AL0670 is regarded as a pinacidil-type K(+)-channel opener, it showed different pharmacological and conformational profiles from pinacidil.

摘要

上一篇论文报道了N-(6-氨基-3-吡啶基)-N'-双环烷基-N"-氰基胍衍生物的合成及药理评价，从中选出三种化合物作为有效的钾通道开放剂。在本研究中，对所选化合物进行了大鼠主动脉钾诱导收缩拮抗作用、正常血压大鼠降压活性以及自发性高血压大鼠利尿活性的测试。这导致对化合物(±)-10进行进一步评估，并选择(+)-N-(6-氨基-3-吡啶基)-N'-[(1S,2R,4R)-双环[2.2.1]庚-2-基]-N"-氰基胍((+)-10)(AL0670)作为抗高血压药物进行开发。尽管AL0670被认为是匹那地尔型钾通道开放剂，但其药理和构象特征与匹那地尔不同。