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  • Title: Novel selective quinazoline inhibitors of endothelin converting enzyme-1.
    Author: Ahn K, Sisneros AM, Herman SB, Pan SM, Hupe D, Lee C, Nikam S, Cheng XM, Doherty AM, Schroeder RL, Haleen SJ, Kaw S, Emoto N, Yanagisawa M.
    Journal: Biochem Biophys Res Commun; 1998 Feb 04; 243(1):184-90. PubMed ID: 9473502.
    Abstract:
    PD 069185 is a highly selective and structurally novel inhibitor of endothelin converting enzyme-1 (ECE-1). PD 069185 is a trisubstituted quinazoline with an IC50 value of 0.9 +/- 0.1 microns for inhibition of human ECE-1 from the solubilized membrane fraction of CHO cells stably transfected with human ECE-1 cDNA. Kinetic analysis revealed that PD 069185 is best fit with a competitive inhibition model with a Ki value of 1.1 +/- 0.1 microns and binds in a reversible manner. The closely related enzyme, ECE-2, is not inhibited at up to 100 microns PD 069185. In addition, PD 069185 at 200-300 microns has little effect on other metalloproteases, such as neutral endopeptidase 24.11, stromelysin, gelatinase A, and collagenase, showing a high ECE-1 specificity. Data are also presented to show that this series of inhibitors are effective in inhibiting ECE-1 in intact cells and in attenuating the increase in perfusion pressure induced by big ET-1 in isolated rat mesentery. These non-peptidic ECE-1 inhibitors should serve as a valuable tool to study the pathophysiological role of endothelin and the therapeutic potential of ECE-1 inhibitors.
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