γ-Carbamate butenolide analogues as potent ETA selective endothelin receptor antagonists and prodrugs

Continued SAR around our ETA selective series of butenolide antagonists, for example PD156707 (1) has yielded a new series of subnanomolar ETA selective antagonists. Depending upon solution pH, 1 exists as the ring closed butenolide form (shown) or as the tautomeric open chain keto-acid salt. Reaction of the butenolide γ-hydroxyl with isocyanates yields carbamates with essentially identical ETA binding affinity and with improved ETA selectivity. As carbamates these derivatives may undergo facile hydrolysis, reverting back to their parent butenolides, and therefore may be useful as prodrugs of 1. Stability studies of PD163140 (7) indicate that the compound is stable in the binding assay conditions and hence has intrinsic activity. In addition 7 is readily hydrolyzed by rat intestinal perfusate to yield the parent compound 1.