Yoshiizumi K, Ikeda S, Goto K, Morita T, Nishimura N, Sukamoto T, Yoshino K
New Drug Discovery Research Laboratory, Kanebo Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 1996 Nov;44(11):2042-50. doi: 10.1248/cpb.44.2042.
3,5-Di-substituted phenylcyanoguanidine derivatives with halogen, cyano and/or nitro groups at the 3- and 5-positions of the benzene ring exhibited very strong smooth muscle relaxation activity in vitro, as compared to pinacidil. Among them, N-(3-chloro-5-cyanophenyl)-N'-cyano-N" -tert-pentylguanidine (5s) showed 27-fold more potent activity than pinacidil, and exhibited a stronger and more lasting antihypertensive effect than pinacidil by oral administration to spontaneously hypertensive rats. We propose a new pharmacophore model in which the essential factors for binding to the potassium channel are an NH and a bulky alkyl group.
在苯环的3-位和5-位带有卤素、氰基和/或硝基的3,5-二取代苯基氰基胍衍生物，与吡那地尔相比，在体外表现出非常强的平滑肌松弛活性。其中，N-(3-氯-5-氰基苯基)-N'-氰基-N''-叔戊基胍(5s)的活性比吡那地尔强27倍，并且通过对自发性高血压大鼠口服给药，其降压作用比吡那地尔更强且更持久。我们提出了一种新的药效团模型，其中与钾通道结合的关键因素是一个NH和一个庞大的烷基。
