Azole endothelin antagonists. 2. Structure-activity studies.

Structure-activity studies have been performed in an attempt to improve the potency of a novel series of azole-based endothelin-A (ET A ) selective antagonists. Modifications of the hydrophobic group on the terminal urea produced substantial effects on receptor affinity ; in particular, the choice of cyclohexyl- or arylureas led to substantial improvements in activity. Conformational restriction of these groups provides an additional benefit. N-Methylation of the indole moiety which is part of the heterocyclic dipeptide surrogate also improves potency. The effects of these two modifications appear to be synergistic, with the best of the resultant doubly modified analogs (e.g. 14q, 15y, and 15ff) exhibiting an 80-200-fold improvement over the original leads.