Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist

J Med Chem. 1997 May 23;40(11):1690-7. doi: 10.1021/jm9700068.


Previously we reported the discovery of amidothiophenesulfonamides as endothelin receptor-A antagonists with high potency and selectivity. Replacement of an amide group in this class of compounds with an acetyl group maintained the in vitro binding affinity and in vivo activity while providing a compound with oral bioavailability and longer duration of action. The optimal compound discovered during these studies, 15q (TBC11251), binds competitively to human ETA receptors with a Ki of 0.43 +/- 0.03 nM and an IC50 of 1.4 nM (IC50 for ETB = 9800 nM). This compound inhibits ET-1-induced stimulation of phosphoinositide turnover with a Ki of 0.686 nM and a pA2 of 8.0. The compound has a serum half-life in the rat and the dog of 6-7 h and 60-100% oral bioavailability. This compound is one of the most selective ETA antagonists reported and therefore is suitable for additional pharmacological and clinical investigation of the role of ETA receptors in diseases.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding, Competitive
  • Biological Availability
  • COS Cells
  • Cell Line
  • Dogs
  • Endothelin Receptor Antagonists*
  • Endothelin-1 / pharmacology
  • Half-Life
  • Humans
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / pharmacokinetics
  • Isoxazoles / pharmacology
  • Male
  • Phosphatidylinositols / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin A
  • Receptors, Endothelin / metabolism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / pharmacokinetics
  • Thiophenes / pharmacology


  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Isoxazoles
  • Phosphatidylinositols
  • Receptor, Endothelin A
  • Receptors, Endothelin
  • Thiophenes
  • sitaxsentan