Structure−Activity Relationships of a Novel Class of Endothelin-A Receptor Antagonists and Discovery of Potent and Selective Receptor Antagonist, 2-(Benzo[1,3]dioxol-5-yl)-6-isopropyloxy-4-(4-methoxyphenyl)-2H-chromene-3- carboxylic Acid (S-1255). 1. Study on Structure−Activity Relationships and Basic Structure Crucial for ET<INF>A</INF> Antagonism

A novel series of endothelin-A (ET<INF>A</INF>) selective receptor antagonists having a 2H-chromene skeleton are described. A lead compound, 2-(benzo[1,3]dioxol-5-yl)-2H-chromene-3-carboxylic acid (<BO>3</BO>), was found by modifications of our own angiotensin II antagonist. A structure−activity relationship (SAR) study of <BO>3</BO> reveals that the structural requirements essential for potent and selective ET<INF>A</INF> receptor binding affinity are the m,p-methylenedioxyphenyl, carboxyl, and isopropoxy groups at the 2-, 3-, and 6-positions, respectively, on the (R)-2H-chromene skeleton. The substituent at the 4-position is also important for improving the activity, and various hydrophobic functional groups of 6−9 Å such as liner, branched, and cyclic aliphatic groups, unsubstituted and substituted aryl groups, and even halogen atoms were acceptable. These results suggest that (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-2H-chromene-3-carboxylic acid, formula <BO>108</BO>, is the crucial basic structure to be recognized by the ET<INF>A</INF> receptor. The most potent compound is (R)-<BO>48</BO> (S-1255), which binds to the ET<INF>A</INF> receptor with an IC<INF>50</INF> value of 0.19 nM and is 630-fold selective for the ET<INF>A</INF> receptor than for the ET<INF>B</INF> receptor. This compound has 55% oral bioavailability in rats. On the basis of the SAR, the roles of each substituent in the receptor binding are discussed.