A Novel Synthetic Inhibitor of Endopeptidase

Abstract A novel synthetic inhibitor of endopeptidase-24.15 (EP-2415, EC 3.4.24.IS), N-[(2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thazolidinecarbonyl]-L-phenylalanine (SA898) is described. This compound inhibited rat EP-24.15 competitively with an IC50 of 23 nM and Ki of 9.1 nM. These values were, respectively, 9.6 times and 6.3 times smaller than those for N-(1 -carboxy-3-phenylpropyl)-alanyl-alanyl-phenylalanyl-p-aminobenzoate (cFP-AAF-pAB), which was one of the most potent inhibitors thus far reported. The inhibitory effect of SA898 on other endopeptidases, angiotensin converting enzyme (ACE, EC.3.4.15.1) and endopeptidase-24.11 (EP-24.11, EC.3.4.24.11) was also studied. SA898 inhibited ACE significantly, but the potency was about 20-fold lower than that for EP-24.15 in terms of the Ki value. The inhibitory effect of SA898 on EP-24.11 was almost negligible (Ki = 28 μM). In addition, the inhibitory activities of several SA898-related compounds were examined. Based on these data, the structure-activity relationships for EP-24.15 inhibitors are discussed.