Syntheses and biological activities of potent potassium channel openers derived from (+/-)-2-oxo-1-pyridin-3-yl-cyclohexanecarbothioic acid methylamide: new potassium channel openers.

doi:10.1021/JM00063A010

Paper

Syntheses and biological activities of potent potassium channel openers derived from (+/-)-2-oxo-1-pyridin-3-yl-cyclohexanecarbothioic acid methylamide: new potassium channel openers.

Published May 28, 1993 · T. Brown, R. Chapman, J. Mason

Journal of medicinal chemistry

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Abstract

The syntheses and biological activities of (+/-)-2-(cyanomethylene)-1-pyridin-3-ylcyclohexanecarbothioic++ + acid methylamide (6) and trans-(+/-)-2-(cyanomethyl)-1-pyridin-3-ylcyclohexanecarbothioic acid methylamide (14) derived from (+/-)-2-oxo-1-pyridin-3-ylcyclohexanecarbothioic acid methylamide (4) are reported. Compounds were tested for antagonism of potassium-induced contraction of de-endothelialized rat aorta. The effects of modification of 6 and 14 on in vitro K(+)-channel opening activity are presented. These new series of potassium channel openers so derived are best exemplified by (+/-)-2-[2-(phenylsulfanyl)ethylidene]-1-pyridin-3-ylcyclohexan ecarbothioic acid methylamide (13d, RP 66266) and trans-(+/-)-2-[2-[(phenylsulfonyl)amino]ethyl]-1-pyridin-3- ylcyclohexanecarbothioic acid methylamide (25a, RP 66784), which have IC90 values of 3 and 0.3 nM, respectively. The potency of the most active compounds indicates a possible interaction at an extra binding site. The compounds described herein are potential antihypertensive and antianginal agents.

In Vitro Study

Study Snapshot

Potent potassium channel openers derived from (+/-)-2-(cyanomethylene)-1-pyridin-3-ylcyclohexanecarbothioic acid methylamide (4) show potential as antihypertensive and antianginal agents.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Syntheses and biological activities of potent potassium channel openers derived from (+/-)-2-oxo-1-pyridin-3-yl-cyclohexanecarbothioic acid methylamide: new potassium channel openers.

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References

Citations

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Palladium-catalyzed cross-coupling of cycloalkanones with heteroaryl bromides under optimal conditions allows efficient reactions with various cycloalkanones, overcoming previous limitations.

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Palladium-catalyzed direct -C(sp3) heteroarylation of ketones under microwave irradiation successfully produces 28 heteroarylated ketones, offering potential for valuable building blocks in medicinal chemistry and chemical industry.

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Pyridinedithioesters can efficiently serve as heterodienophiles, leading to a new synthesis of racemic Aprikalim and potentially new analogues.

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KATP channel openers show potential as promising drug targets for treating various diseases, including type 2 diabetes and muscle relaxation.

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p-Anisolesulfonyl chloride is a versatile sulfonating agent useful for the preparation of sulfonamides or as an N-protecting group2.

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Arylimino-1,2,4-thiadiazolidinones show smooth muscular relaxant properties in rat portal veins, potentially acting through potassium-induced hyperpolarization of vascular smooth cells.

Advances in the structure‐activity relationships, mechanisms of action, and therapeutic utilities of ATP‐sensitive potassium channel openers

Tissue selective KATP openers show promise for treating ischemic heart disease, urinary incontinence, and asthma, but their molecular mechanism of action remains unresolved.