SYNTHESIS AND CONFORMATIONAL-ANALYSIS OF CYCLIC PENTAPEPTIDE ENDOTHELIN ANTAGONISTS

Two endothelin antagonists cycle (D-Leu-D-Val-Pro-D-Asp-Trp) (IPI-147) , and cycle (D-Trp-D-Asp-Ac(3)c-D-Val-Leu) (IPI-725) have been synthes ized. Their solution conformations have been studied in aqueous soluti on by NMR spectroscopy and dynamics simulation. Activity studies show that IPI-725 is a strong ET, antagonist, while IPI-147 is a weak ET, a ntagonist. Comparison of the solution conformations of these two ET, a ntagonists suggests that the difference in their activities results fr om their structural differences. IPI-147 contains a type II beta-turn with a hydrogen bond between NH of D-Val and the C = O of D-Asp. IPI-7 25, on the other hand, contains two turns, a type II beta-turn with a hydrogen bond between NH of D-Asp and C = O of D-Val, as well as a gam ma'-turn with a hydrogen bond formed between D-Val NH and D-Asp carbon yl group. Therefore IPI-147 appears to be more flexible than IPI-725. Although both beta-turns contain the same residues, their orders in th e turn are reversed. The beta-turn in IPI-725 is formed with D-Val:Leu :D-Trp:D-Asp, while in IPI-147, the beta-turn is formed with D-Asp:Trp :D-Leu:D-Val. The activities and solution conformations of IPI-147 and IPI-725 were also compared with BQ-123 [cyclo(D-Trp-D-Asp-Pro-D-Val-L eu)], a well characterized, highly potent endothelin antagonist. (C) M unksgaard 1996.