NOVEL POTASSIUM CHANNEL OPENERS - SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF NEW N-(SUBSTITUTED-3-PYRIDYL)-N-ALKYLTHIOURWEAS AND RELATED-COMPOUNDS

This report describes the synthesis and pharmacological evaluation of a series of novel potassium channel openers related to the pinacidil-t ype compounds. Thioureas, cyanoguanidines, and pyridine N-oxides were systematically evaluated for their effects on both the inhibition of s pontaneous mechanical activity in rat portal vein (in vitro) and their antihypertensive activity (in vivo), and the structure-activity relat ionship for this series of compounds was discussed. Good correlation b etween in vitro and iv antihypertensive activity was observed for thes e compounds. Among them, cyanoguanidines bearing a conformationally ri gid unit such as a norbornyl group generally possessed potent activity in both in vitro and in vivo studies. Especially, idyl)-N'-cyano-N''- (1-methyl-2-norbornyl)guanidine (23d) was identified as a more potent potassium channel opener in vitro (EC(100) = 3 x 10(-8) M) than pinaci dil (EC(100) = 10(-7) M).