Selective endothelin A receptor antagonists. 4. Discovery and structure-activity relationships of stilbene acid and alcohol derivatives.

This publication describes the synthesis and optimization of a novel series of stilbene endothelin antagonists. Analysis of the SAR established for previous papers in this series prompted the design and synthesis of (Z)-4-phenyl-5-(3-benzyloxyphenyl)pent-4-enoic acid 3 which was found to be a moderately active inhibitor of the binding of [ 125 I]ET-1 to ET A receptors with an IC 50 of 6 μM. More interestingly, the intermediate compound (E)-2-phenyl-3-(3-benzyloxyphenyl)-propenoic acid 5 was equiactive with 3. Optimization of 5 resulted in the preparation of (E)-2-phenyl-3-(2-cyano-5-(thien-3-ylmethoxy))phenylpropenoic acid 18 (RPR111723) which had an IC 50 in the binding assay of 80 nM on the ET A receptor and a pK B of 6.5 in the functional assay, measured on rat aortic strips. Reduction of the acid group of 5 gave the first nonacidic ET A antagonist in our series, (E)-2-phenyl-3-(3-benzyloxyphenoxy)prop2-enol 6 with an IC 50 of 20 μM. Optimization of 6 resulted in the preparation of 2-(2-methylphenyl)-3-(2-cyano-5-(thien-3-ylmethyl)phenyl)prop-2-enol 33 with an IC 50 of 300 nM on the ET A receptor.