Discovery of endothelin antagonists

Novel cyclic pentapeptides, WS7338A, B, C and D [cyclo-(AAl -AA2-DTrp-D-Glu-Ala)] were isolated as Endothelin (ET) receptor antagonists from the culture broth of Sfreptomyces sp. No. 7338. Based on conformational analysis of these seeds, we defined the minimum structural requirements for binding affinity and prepared a series of acylated tripeptides with ETA receptor binding affinity. Through extensive chemical modification of the lead tripeptide, we have discovered a highly potent and selective ETA receptor antagonist FR139317. Further modification of this series of tripeptide ET antagonists has led to the discovery of a highly potent and selective ETB receptor antagonist FR164343. The discovery and structure-activity relationship of these ET antagonists and the pharmacological profile of FR139317 and FR164343 are described.