STRUCTURE-ACTIVITY RELATIONSHIP OF PHOSPHORAMIDON DERIVATIVES FOR IN-VIVO ENDOTHELIN-CONVERTING-ENZYME INHIBITION

The structure activity relationship of phosphoramidon analogues was st udied for their ability to reduce the hypertensive effect of exogenous proET-1, probably via inhibition of an endothelin converting enzyme a ctivity (ECE). Results concerning in vivo ECE and in vitro thermolysin inhibitions were compared. In contrast to the phosphoryl group of pho sphoramidon, which was found to be an absolute requirement, the rhamno se moiety was of very little importance for the inhibition of either e nzyme. Furthermore, the tryptophan residue of phosphoramidon appeared to be particularly important for the ECE inhibition, whereas thermolys in inhibition seemed to depend greatly on the leucine residue. It is c oncluded that in vivo ECE and thermolysin differ in the way they recog nise phosphoramidon. The existence of an hydrophobic pocket, specific for the recognition of the tryptophan residue of phosphoramidon, could be proposed for ECE.