PYRROLIDINE-3-CARBOXYLIC ACIDS AS ENDOTHELIN ANTAGONISTS .2. SULFONAMIDE-BASED ETA ETB MIXED ANTAGONISTS/

When the N,N-dialkylacetamide side chain of the highly ETA-selective e ndothelin antagonist ABT-627 (1; utylamino)carbonyl]methyl]pyrrolidine -3-carboxylic acid; A-147627) is replaced by N,S-dialkylsulfonamidoeth yl, the resultant analogs retain ETA affinity, but exhibit substantial ETB affinity as well. Structure-activity studies reveal that modifica tions in the length of the two alkyl groups, and in the substitution o n the anisyl ring, are important in optimizing this ''balanced'' antag onist profile. In particular the combination of an N-n-propyl group, a n S-alkyl chain between four and six carbons in length, and a fluorine atom ortho to the aromatic OCH3 provides compounds with sub-nanomolar affinities for both receptor subtypes, and with ETA/ETB ratios close to 1. A number of these compounds also exhibit oral bioavailabilities (in rats) in the 30-50% range and have substantial plasma half-lives. The balanced receptor-binding profile of these potent and orally bioav ailable compounds complements the ETA selectivity observed with 1.