title: Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ET(B) selectivity.
abstract: 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.
authors.affiliation: Metabolic Disease Research and Drug Analysis Department, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. thomas.vongeldern@abbott.com
authors.forename: T W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: A S
authors.initials: AS
authors.lastname: Tasker
authors.forename: B K
authors.initials: BK
authors.lastname: Sorensen
authors.forename: M
authors.initials: M
authors.lastname: Winn
authors.forename: B G
authors.initials: BG
authors.lastname: Szczepankiewicz
authors.forename: D B
authors.initials: DB
authors.lastname: Dixon
authors.forename: W J
authors.initials: WJ
authors.lastname: Chiou
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: J L
authors.initials: JL
authors.lastname: Wessale
authors.forename: A
authors.initials: A
authors.lastname: Adler
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: B
authors.initials: B
authors.lastname: Nguyen
authors.forename: T J
authors.initials: TJ
authors.lastname: Opgenorth
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B
chemical_list: C120508:A 192621; D000083:Acetanilides; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044023:Receptor, Endothelin B; D000077868:Atrasentan