2,4-DIARYLPYRROLIDINE-3-CARBOXYLIC ACIDS POTENT ETA-SELECTIVE ENDOTHELIN RECEPTOR ANTAGONISTS .1. DISCOVERY OF A-127722

We have discovered a novel class of endothelin (ET) receptor antagonis ts through pharmacophore analysis of the existing non-peptide ET antag onists. On the basis of this analysis, we determined that a pyrrolidin e ring might replace the indan ring in SE 209670. The resultant compou nds were readily prepared and amenable to extensive SAR studies. Thus a series of N-substituted trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol -5-yl) pyrrolidine-3-carboxylic acids (8) have been synthesized and ev aluated for binding at ET(A) and ET(B) receptors. Compounds with N-acy l and simple N-alkyl substituents had weak activity. Compounds with N- alkyl substituents containing ethers, sulfoxides, or sulfones showed i ncreased activity. Much improved activity resulted from compounds wher e the N-substituents were acetamides. Compound 17u (A-127722) with the N,N-dibutylacetamide substituent is the best of the series. It has an IC50 = 0.36 nM for inhibition of ET-1 radioligand binding at the ETA( A) receptor, with a 1000-fold selectivity for the ET(A) vs the ET(B) r eceptor. It is also a potent inhibitor (IC50 = 0.16 nM) of phosphoinos itol hydrolysis stimulated by ET-1, and it antagonized the ET-l-induce d contraction of the rabbit aorta with a pA(2) = 9.20. The compound ha s 70% oral bioavailability in rats.