Design, synthesis, and activity of a series of pyrrolidine-3-carboxylic acid-based, highly specific, orally active ETB antagonists containing a diphenylmethylamine acetamide side chain

The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and mediates both vasodilation and vasoconstrictio n. On the basis of the pharmacophore of the previously reported ETA-specifi c antagonist 1, (ABT-627), we are reporting the discovery of a novel series of highly specific, orally active ETB receptor antagonists. Replacing the dibutylaminoacetamide group of 1 with a diphenylmethylaminoacetamide group resulted in antagonist 2 with a complete reversal of receptor specificity. Structure-activity relationship studies revealed that ortho-alkylation of t he phenyl rings could further increase ETB affinity and also boost the ETA/ ETB activity ratio of the resulting antagonists. A similar antagonism selec tivity profile could also be achieved when one of the phenyl rings of the a cetamide side chain was replaced with an alkyl group, preferably a tert-but yl group,(10h). Combining these features with modification of the a-aryl gr oup of the pyrrolidine core, we have identified a potent antagonist (9k, A- 308165) with over 27 000-fold selectivity favoring the ETB receptor and an acceptable pharmacokinetic profile (F = 24%) in rats.