Endothelin Receptor Antagonists

In our effort to obtain antagonists of the ET receptors, rational design based on agonist structure played a crucial part in the strategy that led to SB 209670. In vivo pharmacological studies with SB 209670, both in our own laboratories and through the work of others, have done much to elucidate potential roles for ET in the etiology of disease and to establish the therapeutic potential of ET receptor antagonists. Hampered in our search for an orally effective agent by the poor bioavailability of SB 209670, intestinal permeability screening was used to discover SB 217242, an antagonist with excellent oral characteristics. The key contributions outlined above toward the design of SB 217242 emphasize the multi-disciplinary approach used in today’s drug discovery efforts.