NOVEL SELECTIVE QUINAZOLINE INHIBITORS OF ENDOTHELIN-CONVERTING ENZYME-1

PD 069185 is a highly selective and structurally novel inhibitor of en dothelin converting enzyme-1 (ECE-1). PD 069185 is a trisubstituted qu inazoline with an IC50 value of 0.9 +/- 0.1 mu M for inhibition of hum an ECE-1 from the solubilized membrane fraction of CHO cells stably tr ansfected with human ECE-1 cDNA. Kinetic analysis revealed that PD 069 185 is best fit with a competitive inhibition model with a K-i value o f 1.1 +/- 0.1 mu M and binds in a reversible manner. The closely relat ed enzyme, ECE-2, is not inhibited at up to 100 mu M PD 069185. In add ition, PD 069185 at 200-300 mu M has little effect on other metallopro teases, such as neutral endopeptidase 24.11, stromelysin, gelatinase A , and collagenase, showing a high ECE-1 specificity. Data are also pre sented to show that this series of inhibitors are effective in inhibit ing ECE-1 in intact cells and in attenuating the increase in perfusion pressure induced by big ET-1 in isolated rat mesentery. These non-pep tidic ECE-1 inhibitors should serve as a valuable tool to study the pa thophysiological role of endothelin and the therapeutic potential of E CE-1 inhibitors. (C) 1998 Academic Press.