Abstract
The synthesis and structure activity relationships of a series of N-pyrimidinyl benzenesulfonamides as ETB selective antagonists are described. N-Isoxazolyl benzenesulfonamide 1a, previously reported, (1) was selected as a lead compound, and isosteric replacement of the isoxazole ring of 1a with a pyrimidine ring led to the discovery of the highly potent ETB selective antagonist 6e with oral bioavailability. Modification of the terminal aldehyde group at the 6-position of the pyrimidine ring was investigated, and malonate 15b and acylhydrazone 16f were found to be equipotent to aldehyde 6e. Compound 6e showed ETB antagonistic activity on in vivo evaluation.
MeSH terms
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Aldehydes / chemistry
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Animals
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Aorta, Thoracic / drug effects
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Aorta, Thoracic / metabolism
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Area Under Curve
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Blood Pressure / drug effects
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COS Cells
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Crystallography, X-Ray
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Endothelin Receptor Antagonists*
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Endothelin-1 / antagonists & inhibitors
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Male
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Models, Molecular
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Muscle Contraction / drug effects
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Muscle, Smooth, Vascular / drug effects
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Receptor, Endothelin B
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Structure-Activity Relationship
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Sulfonamides / chemistry
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology*
Substances
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Aldehydes
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Endothelin Receptor Antagonists
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Endothelin-1
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Pyrimidines
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Receptor, Endothelin B
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Sulfonamides