Thieno[2, 3-d]pyrimidine-3-acetic Acids A New Class of Nonpeptide Endothelin Receptor Antagonists

抄録

On the basis of structural information for the cyclic hexapeptide endothelin (ET) receptor antagonist, TAK-044, a series of thieno[2, 3-d]pyrimidine-2, 4-dione derivatives bearing a carboxyl group and aromatic rings that were important for receptor binding were designed, synthesized, and evaluated for ET receptor binding affinities and inhibitory activities against ET-induce vasconstriction.Optimization of each substituent in the thieno[2, 3-d]pyrimidine ring led to the discovery of a novel and potent nonpeptide ET receptor antagonist, 6-(4-methoxymethoxyphenyl)-5-methylsulafonylminomethyl-1-(2-methylthiobenzyl)-2, 4-dioxo-1, 2, 3, 4-tetrahydrothieno[2, 3-d]pyrimidine-3-acetic acid (32 g), which binded to human ET_A and ET_B receptor subtypes with affinities (IC₅₀) of 7.6 and 100 nM, respectively.Compound 32 g effectively antagonized ET-induced vasconstriction and the inhibitory effect mediated by the ET_B receptor was more potent than that of bosentan, while the inhibitory effect mediated by the ET_A receptor was slightly less potent than that of bosentan.