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-induced vasoconstriction. 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- methylsulfonylaminomethyl-1-(2-methylthiobenzyl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidine-3-acetic acid (32g), 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 vasoconstriction 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.
- ET-induced vasoconstriction
- Endothelin receptor antagonist
- Endothelin receptor binding affinity
- Thieno[2,3-d]pyrimidine-3-acetic acid
ASJC Scopus subject areas
- Drug Discovery