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

概要

論文の詳細を見る
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 (IC_<50>) 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.
公益社団法人日本薬学会の論文
1998-11-15