Novel potassium channel openers: synthesis and pharmacological evaluation of new N-(substituted-3-pyridyl)-N'-alkylthioureas and related compounds

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 mechanica...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-01, Vol.37 (1), p.18-25
Main Authors: Takemoto, Tadahiro, Eda, Masahiro, Hihara, Mitsuyoshi, Okada, Takehiro, Sakashita, Hiroshi, Eiraku, Miyuki, Matzno, Sumio, Gohda, Maki, Ebisu, Hajime
Format: Article
Language:English
Subjects:
4-Aminopyridine - analogs & derivatives
4-Aminopyridine - chemistry
4-Aminopyridine - pharmacology
Amifampridine
Animals
Antihypertensive Agents - chemical synthesis
Antihypertensive Agents - therapeutic use
Biomechanical Phenomena
Chemistry
Exact sciences and technology
Glyburide - pharmacology
Guanidines - chemistry
Guanidines - pharmacology
Heterocyclic compounds
Heterocyclic compounds with only one n hetero atom and condensed derivatives
Hypertension - drug therapy
Male
Molecular Structure
Norbornanes - chemistry
Norbornanes - pharmacology
Organic chemistry
Pinacidil
Portal Vein - drug effects
Portal Vein - physiology
Potassium Channels - drug effects
Preparations and properties
Rats
Rats, Inbred SHR
Rats, Wistar
Structure-Activity Relationship
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Summary: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).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00027a003