title: Novel potassium channel openers: synthesis and pharmacological evaluation of new N-(substituted-3-pyridyl)-N'-alkylthioureas and related compounds.
abstract: This report describes the synthesis and pharmacological evaluation of a series of novel potassium channel openers related to the pinacidil-type compounds. Thioureas, cyanoguanidines, and pyridine N-oxides were systematically evaluated for their effects on both the inhibition of spontaneous mechanical activity in rat portal vein (in vitro) and their antihypertensive activity (in vivo), and the structure-activity relationship for this series of compounds was discussed. Good correlation between in vitro and iv antihypertensive activity was observed for these compounds. Among them, cyanoguanidines bearing a conformationally rigid unit such as a norbornyl group generally possessed potent activity in both in vitro and in vivo studies. Especially, N-(6-amino-3-pyridyl)-N'-cyano-N"-(1-methyl-2-norbornyl)guanidine (23d) was identified as a more potent potassium channel opener in vitro (EC100 = 3 x 10(-8) M) than pinacidil (EC100 = 10(-7) M).
authors.affiliation: Research Division, Green Cross Corporation, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takemoto
authors.forename: M
authors.initials: M
authors.lastname: Eda
authors.forename: T
authors.initials: T
authors.lastname: Okada
authors.forename: H
authors.initials: H
authors.lastname: Sakashita
authors.forename: S
authors.initials: S
authors.lastname: Matzno
authors.forename: M
authors.initials: M
authors.lastname: Gohda
authors.forename: H
authors.initials: H
authors.lastname: Ebisu
authors.forename: N
authors.initials: N
authors.lastname: Nakamura
authors.forename: C
authors.initials: C
authors.lastname: Fukaya
authors.forename: M
authors.initials: M
authors.lastname: Hihara
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000077770:Amifampridine; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D001696:Biomechanical Phenomena; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D015394:Molecular Structure; D009636:Norbornanes / Q000737:chemistry* / Q000494:pharmacology*; D020110:Pinacidil; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000959:Antihypertensive Agents; D006146:Guanidines; D009636:Norbornanes; D015221:Potassium Channels; C085365:N-(6-amino-3-pyridyl)-N'-cyano-N''-(1-methyl-2-norbornyl)guanidine; D020110:Pinacidil; D015761:4-Aminopyridine; D000077770:Amifampridine; D005905:Glyburide