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

✍ Scribed by William C. Patt; Billy R. Reisdorph; Joseph T. Repine; Annette M. Doherty; Stephen J. Haleen; Donnelle M. Walker; Kathleen M. Welch; Michael A. Flynn; Hussein Hallak; Eric L. Reyner; Barbra H. Stewart

• Book ID: 104364820
• Publisher: Elsevier Science
• Year: 1997
• Tongue: English
• Weight: 272 KB
• Volume: 7
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/s0960-894x(97)00002-4

✦ Synopsis

Continued SAR around our ET A selective series of butenolide antagonists, for example PD156707 (1) has yielded a new series of subnanomolar ET A 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 y-hydroxyl with isocyanates yields carbamates with essentially identical ET A binding affinity and with improved ET A 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.