Novel selective quinazoline inhibitors of endothelin converting enzyme-1

Kyunghye Ahn; Andre M. Sisneros; Sarah B. Herman; Sharon M. Pan; Donald Hupe; Chitase Lee; Sham Nikam; Xue Min Cheng; Annette M. Doherty; Richard L. Schroeder; Stephen J. Haleen; Semiko Kaw; Noriaki Emoto; Masashi Yanagisawa

doi:10.1006/bbrc.1998.8081

Novel selective quinazoline inhibitors of endothelin converting enzyme-1

Kyunghye Ahn, Andre M. Sisneros, Sarah B. Herman, Sharon M. Pan, Donald Hupe, Chitase Lee, Sham Nikam, Xue Min Cheng, Annette M. Doherty, Richard L. Schroeder, Stephen J. Haleen, Semiko Kaw, Noriaki Emoto, Masashi Yanagisawa

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51 Scopus citations

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 μM 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 K(i) value of 1.1 ± 0.1 μM and binds in a reversible manner. The closely related enzyme, ECE-2, is not inhibited at up to 100 μM PD 069185. In addition, PD 069185 at 200-300 μM 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.

Original language	English (US)
Pages (from-to)	184-190
Number of pages	7
Journal	Biochemical and Biophysical Research Communications
Volume	243
Issue number	1
DOIs	https://doi.org/10.1006/bbrc.1998.8081
State	Published - Feb 4 1998

Keywords

Big endothelin
Endothelin
Endothelin converting enzyme
Quinazoline

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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10.1006/bbrc.1998.8081

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Ahn, K., Sisneros, A. M., Herman, S. B., Pan, S. M., Hupe, D., Lee, C., Nikam, S., Cheng, X. M., Doherty, A. M., Schroeder, R. L., Haleen, S. J., Kaw, S., Emoto, N., & Yanagisawa, M. (1998). Novel selective quinazoline inhibitors of endothelin converting enzyme-1. Biochemical and Biophysical Research Communications, 243(1), 184-190. https://doi.org/10.1006/bbrc.1998.8081

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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 μM 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 K(i) value of 1.1 ± 0.1 μM and binds in a reversible manner. The closely related enzyme, ECE-2, is not inhibited at up to 100 μM PD 069185. In addition, PD 069185 at 200-300 μM 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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author = "Kyunghye Ahn and Sisneros, {Andre M.} and Herman, {Sarah B.} and Pan, {Sharon M.} and Donald Hupe and Chitase Lee and Sham Nikam and Cheng, {Xue Min} and Doherty, {Annette M.} and Schroeder, {Richard L.} and Haleen, {Stephen J.} and Semiko Kaw and Noriaki Emoto and Masashi Yanagisawa",

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AU - Ahn, Kyunghye

AU - Sisneros, Andre M.

AU - Herman, Sarah B.

AU - Pan, Sharon M.

AU - Hupe, Donald

AU - Lee, Chitase

AU - Nikam, Sham

AU - Cheng, Xue Min

AU - Doherty, Annette M.

AU - Schroeder, Richard L.

AU - Haleen, Stephen J.

AU - Kaw, Semiko

AU - Emoto, Noriaki

AU - Yanagisawa, Masashi

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N2 - 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 μM 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 K(i) value of 1.1 ± 0.1 μM and binds in a reversible manner. The closely related enzyme, ECE-2, is not inhibited at up to 100 μM PD 069185. In addition, PD 069185 at 200-300 μM 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.

AB - 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 μM 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 K(i) value of 1.1 ± 0.1 μM and binds in a reversible manner. The closely related enzyme, ECE-2, is not inhibited at up to 100 μM PD 069185. In addition, PD 069185 at 200-300 μM 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.

KW - Big endothelin

KW - Endothelin

KW - Endothelin converting enzyme

KW - Quinazoline

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Novel selective quinazoline inhibitors of endothelin converting enzyme-1

Abstract

Keywords

ASJC Scopus subject areas

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