Synthesis and biological activity of trans-(.+-.)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamide 1-oxide (RP 49356) and analogs: a new class of potassium channel opener

The synthesis and biological activity of trans-(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamid+ ++ e 1-oxide (8a, RP 49356) and analogues is reported. These compounds constitute a new structural class of K(+)-channel opener. The effects of changes in pyridyl group, thioamide, and thia...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1992-10, Vol.35 (20), p.3613-3624
Main Authors: Brown, Thomas J, Chapman, Robert F, Cook, David C, Hart, Terance W, McLay, Iain M, Jordan, Roy, Mason, Jonathan S, Palfreyman, Malcolm N, Walsh, Roger J. A
Format: Article
Language:English
Subjects:
Animals
Antihypertensive Agents - chemical synthesis
Antihypertensive Agents - chemistry
Antihypertensive Agents - pharmacology
Blood Pressure - drug effects
Dogs
Male
Molecular Conformation
Picolines - chemical synthesis
Picolines - chemistry
Picolines - pharmacology
Potassium Channels - drug effects
Pyrans - chemical synthesis
Pyrans - chemistry
Pyrans - pharmacology
Rats
Rats, Sprague-Dawley
Stereoisomerism
Structure-Activity Relationship
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Summary:The synthesis and biological activity of trans-(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamid+ ++ e 1-oxide (8a, RP 49356) and analogues is reported. These compounds constitute a new structural class of K(+)-channel opener. The effects of changes in pyridyl group, thioamide, and thiane ring on in vitro K(+)-channel opening reactivity are discussed. A 3-pyridyl or 3-quinolyl group, a small N-alkyl thioamide function, and a thiane oxide ring, in which the sulfoxide is in a trans relationship to the thioamide, are preferred for activity. Selected compounds were tested intravenously in the normotensive anaesthetized rat for hypotensive effects, and the activities reflect their in vitro K(+)-channel opening activity. This led to further evaluation of compound 8a and the selection of the (-)-enantiomer 8b (RP 52891) for development as an antihypertensive and antianginal agent.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00098a004