Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ET(B) 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.
von Geldern
T W
TW
Metabolic Disease Research and Drug Analysis Department, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. thomas.vongeldern@abbott.com
Tasker
A S
AS
Sorensen
B K
BK
Winn
M
M
Szczepankiewicz
B G
BG
Dixon
D B
DB
Chiou
W J
WJ
Wang
L
L
Wessale
J L
JL
Adler
A
A
Marsh
K C
KC
Nguyen
B
B
Opgenorth
T J
TJ
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
C120508:A 192621; D000083:Acetanilides; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044023:Receptor, Endothelin B; D000077868:Atrasentan