Endothelin receptor antagonists
Endothelin receptor antagonists, by blocking the vasoconstrictor and cardiotonic effects of ET-1, produce vasodilation and cardiac inhibition. Endothelin receptor antagonists have been shown to decrease mortality and improve thermodynamics in experimental models of heart failure 1.
Novel cyclic pentapeptides, WS7338A, B, C and D [cyclo-(AAl -AA2-D-Trp-D-Glu-Ala)] were isolated as ET-receptor antagonists from the culture broth of Sfreptomyces sp. No. 7338 2.
Based on conformational analysis, the minimum structural requirements for binding affinity was defined by Neya et al., and a series of acylated tripeptides with ET-A receptor binding affinity were synthesized. Through extensive chemical modification of the lead tripeptide, a potent and selective ETA receptor antagonist FR139317 was discovered. Further modification of this series of tripeptide ET antagonists has led to the discovery of a highly potent and selective ET-B receptor antagonist FR164343 2.
Cyclic pentapeptide endothelin receptor antagonists:WS7338A: 1 cyclo-(D-Val-Leu-D-Trp-D-Glu-Ala)
WS7338B: 2 cyclo-(D-allolle-Leu-D-Trp-D-Glu-Ma)
WS7338C: 3 cyclo-(D-Val-Val-D-Trp-D-Glu-Ala)
WS7338D: 4 cyclo-(D-Leu-Val-D-Trp-D-Glu-Ala)
Through extensive modification of the cyclic pentapeptide 2 on the basis of its conformation analysis a series of tripeptide ET receptor antagonists with ETA and ETB subtype-selectivity were discovered. Further in vivo characterization demonstrated that FR139317 is a highly potent and selective ET-A receptor antagonist, whereas FR164343 is a highly potent and selective ET-B receptor antagonist. It may be concluded that FR139317 and FR164343 are useful pharma- cological agents for investigating the pathophysiological roles of the ET system 2.
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