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

When the dialkylacetamide side chain of the ET A -selective antagonist ABT-627 is replaced with a 2,6-dialkylacetanilide, the resultant analogues show a complete reversal of receptor selectivity, preferring ET B over ET A . By optimizing the aniline substitution pattern, as well as the alkoxy group on the 2-aryl substituent, it is possible to prepare antagonists with subnanomolar affinity for ET B 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 ET B receptor in modulating blood pressure; the observed hypertensive response to persistent ET B blockade is consistent with previous postulates and indicates that ET B -selective antagonists may not be suitable as agents for long-term systemic therapy.