THE DISCOVERY OF NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS - PROGRESSION TOWARDS BOSENTAN

Since its discovery, endothelin-l has attracted considerable scientifi c interest for its extremely potent and long-lasting vasoconstrictor e ffect and its binding to G-protein-coupled receptors. The endothelins appear to be part of a functional regulatory system in the circulation and strong evidence has accumulated for their involvement in clinical disorders associated with vasoconstriction (e.g. renal failure, conge stive heart failure). In a program aimed at identifying nonpeptide ET receptor antagonists, a distinct class of substituted arylsulfonamido pyrimidines was discovered from a chemical substance library. Lead opt imization led to orally active antagonists of ET(A) and ET(B) receptor s possessing mixed or receptor-subtype-selective profiles in the low n anomolar range. From these compounds, the mixed antagonist bosentan wa s selected for development; it shows efficacy in several pathophysiolo gical models of local and systemic vasoconstriction and promising clin ical results in patients suffering from congestive heart failure. Chem ical modifications in this structural class in combination with X-ray crystal data analysis for key compounds led to more in-depth understan ding of antagonist-receptor interaction. Structural determinants of bo sentan binding to the ETA receptor were defined on the molecular level by site-directed mutagenesis experiments. This led to a 3D model of t he antagonist binding domain which proved valuable to rationalize stru cture-activity relationships.