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.


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.

MeSH terms

  • Acetanilides / chemical synthesis*
  • Acetanilides / pharmacology
  • Animals
  • Atrasentan
  • Blood Pressure / drug effects
  • Cell Line
  • Endothelin Receptor Antagonists*
  • Endothelin-1 / pharmacology
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin B


  • A 192621
  • Acetanilides
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Pyrrolidines
  • Receptor, Endothelin B
  • Atrasentan