Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ETB selectivity

When the dialkylacetamide side chain of the ETA-selective antagonist ABT-62 7 is replaced with a 2,6-dialkylacetanilide, the resultant analogues show a complete reversal of receptor selectivity, preferring ETB over ETA. By opt imizing the aniline substitution pattern, as well as the alkoxy group on th e 2-aryl substituent, it is possible to prepare antagonists with subnanomol ar affinity for ETB and with selectivities in excess of 4000-fold. A number of these compounds also show promising pharmacokinetic profiles; a useful balance of properties is found in A-192621 (38). Pharmacology studies with A-192621 serve to reveal the role of the ETB receptor in modulating blood p ressure; the observed hypertensive response to persistent ETB blockade is c onsistent with previous postulates and indicates that ETB-selective antagon ists may not be suitable as agents for long-term systemic therapy.