THE EFFECTS OF DIMINISHING ALBUMIN-BINDING TO SOME ENDOTHELIN RECEPTOR ANTAGONISTS

As a pharmacological class, Endothelin-A receptor (ETA) antagonists ar e highly bound (>98%) to serum albumin. In the presence of physiologic al concentrations of albumin, their affinities for ETA decrease 10 to 100 fold. We have prepared ETA antagonists which exhibit lower degrees of binding to albumin, while maintaining potency and selectivity for the ETA receptor. The protein induced IC50 shift is reduced or elimina ted in this new series of compounds. The compounds also display altere d in vivo and pharmacokinetic profiles which may be consistent with th eir lower degree of protein binding.