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

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 ETA and ETB 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 ETB receptor was more potent than that of bosentan, while the inhibitory effect mediated by the ETA receptor was slightly less potent than that of bosentan.