Synthesis and structure-activity relationships of novel phenylcyanoguanidine derivatives as potassium channel openers.
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.
Yoshiizumi
K
K
New Drug Discovery Research Laboratory, Kanebo Ltd., Osaka, Japan.
Ikeda
S
S
Goto
K
K
Morita
T
T
Nishimura
N
N
Sukamoto
T
T
Yoshino
K
K
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000494:pharmacology
D006146:Guanidines; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D014665:Vasodilator Agents; D020110:Pinacidil; D005905:Glyburide