Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ET(B) selectivity

  • J Med Chem. 1999 Sep 9;42(18):3668-78. doi: 10.1021/jm990170q.
T W von Geldern  1 ,  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
Affiliations
  • 1. Metabolic Disease Research and Drug Analysis Department, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. [email protected]
PMID: 10479298 DOI: 10.1021/jm990170q
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.

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