Abstract
We report here that N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides are potent and selective small molecule ETA receptor antagonists. The aryl group was subjected to extensive structural modification. With monosubstitution, the para position was most useful in increasing potency, with methyl being preferred. With disubstitution, 2,4-disubstitution further enhanced activity with methyl or cyano groups being preferred at the 2-position. In this series, a benzo-[d][1,3]dioxole group is equivalent to a 4-methyl group in in vitro activity and afforded the compounds with both in vivo activity and moderate half-lives.
MeSH terms
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Animals
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Binding, Competitive
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Blood Pressure / drug effects
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COS Cells
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Cell Line
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Endothelin Receptor Antagonists*
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Endothelin-1 / metabolism
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Endothelins / metabolism
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Half-Life
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Humans
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Hydrolysis
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Isoxazoles / chemistry*
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Isoxazoles / pharmacokinetics
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Isoxazoles / pharmacology*
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Male
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Molecular Structure
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Phosphatidylinositols / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptor, Endothelin A
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Receptors, Endothelin / metabolism
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Structure-Activity Relationship
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Thiophenes* / chemistry*
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Thiophenes* / pharmacokinetics
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Thiophenes* / pharmacology*
Substances
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Endothelin Receptor Antagonists
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Endothelin-1
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Endothelins
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Isoxazoles
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Phosphatidylinositols
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Receptor, Endothelin A
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Receptors, Endothelin
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Thiophenes