A novel class of endothelin-A receptor antagonists, (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropyloxy-2H-chromene-3-carboxylic acids (S-1255). Conformational analysis of basic structure, crucial for ETA antagonism, in solution and solid states

Abstract Conformational studies of potent and selective endothelin-A (ET A ) receptor antagonists, 4-substituted ( R )-2-(benzo[1,3]-dioxol-5-yl)-6-isopropoxy-2 H -chromene-3-carboxylic acids, are reported. X-ray crystallography and NMR studies of the 4-anisyl derivative 2 (S-1255), the stable atropisomers 3 and the 4- n -butyl derivative 4 reveal that the A-, B- and C-rings in these compounds adopt a L-like conformation in both solution and solid states. Molecular mechanics calculation shows that this L-like conformation is an inevitable conformation as determined by intramolecular steric repulsions. These 2 H -chromene derivatives bound to an ET A receptor with IC 50 values of less than 1 nM, whereas the dihydro compounds 7 and 9 not having the L-like conformation showed weaker affinities. These results suggest that the L-like conformation is specifically recognized by the active site of the ET A receptor. The roles of the L-like conformation in the receptor binding are discussed.