| Literature DB >> 10479298 |
T W von Geldern1, A S Tasker, B K Sorensen, M Winn, B G Szczepankiewicz, D B Dixon, W J Chiou, L Wang, J L Wessale, A Adler, K C Marsh, B Nguyen, T J Opgenorth.
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.Entities:
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Year: 1999 PMID： 10479298 DOI： 10.1021/jm990170q
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446