Novel Selective Quinazoline Inhibitors of Endothelin Converting Enzyme-1

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

doi:10.1006/bbrc.1998.8081

Cited by 45 publications

(34 citation statements)

References 42 publications

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“…Small molecular biaryl compounds are potential ECE inhibitors [85]. Quinazoline compounds also have potent ECE inhibitory effects [86]. An alternative way to treat hypertension is to take a genetic approach and knock-out a specific ET isoform or ET receptor subtype.…”

Section: Current and Future Developmentsmentioning

confidence: 99%

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Hynynen

Khalil²

2006

PRC

105

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The discovery of endothelin two decades ago has now evolved into an intricate vascular endothelin (ET) system. Several ET isoforms, receptors, signaling pathways, agonists, antagonists, and clinical applications have been identified and documented in first-rate patents. The role of ET as one of the most potent endothelium-derived vasoconstricting factors is now complemented by a newly discovered role in vascular relaxation. ET synthesis is initiated by the transcription of ET genes in endothelial cells and the generation of the gene products preproET and big ET, which are further cleaved by specific ET converting enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind with different affinities to ET A and ET B2 receptors in vascular smooth muscle, and stimulate [Ca 2+ ] i , protein kinase C, mitogen-activated protein kinase and other signaling mechanisms of smooth muscle contraction, growth and proliferation. ET also binds to endothelial ET B1 receptors, which mediate the release of vasodilator substances such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor. Endothelial ET B1 receptors may also function in ET re-uptake and clearance. Although the effects of ET on vascular function and growth are well-recognized, the role of ET and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension is not clearly established. Salt-dependent hypertension in experimental animals and some forms of moderate to severe hypertension in human may show elevated levels of plasma or vascular ET; however, other forms of hypertension show normal ET levels. The currently available ET receptor antagonists reduce blood pressure in some forms of experimental hypertension. Careful examination of recent patents may identify more effective and specific modulators of the vascular ET system for clinical use in human hypertension.

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Section: Current and Future Developmentsmentioning

confidence: 99%

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Hynynen

Khalil²

2006

PRC

105

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“…ELISA Analysis of solECE-1-mediated A␤40 and A␤42 Degradation-SolECE-1 was preincubated for 15 min at room temperature with the ECE inhibitor PD069185 (synthesized according to published methods (38) by the Organic Chemistry Core Facility at the Mayo Clinic Jacksonville) or phosphoramidon (150 M) or an equal volume of vehicle (Me 2 SO and phosphate-buffered saline, respectively), prior to incubation with synthetic A␤40 or A␤42 (0.01 M) in 50 mM MES, pH 6.5, containing 0.01% C 12 E 10 , 1 mM PMSF, 100 M leupeptin, and 20 M pepstatin. The amount of solECE used in this reaction was estimated to be ϳ6 nM.…”

Section: Measurement Of Ece Activity In Cell Membranementioning

confidence: 99%

“…This reduction was completely blocked by incubation with phosphoramidon and also with a more selective ECE-1 inhibitor, PD069185. (This inhibitor, while very useful for in vitro studies, is not informative in cell-based studies due to its toxicity (38)). To confirm that the loss of A␤ was indeed due to A␤ catabolism and not to A␤ binding or some other phenomenon, we analyzed the effect of solECE-1 on A␤ by HPLC with a radiolabeled A␤ reporter molecule.…”

Section: Fig 4 Removal Of Exogenous Synthetic A␤ By Ece-overexpressmentioning

confidence: 99%

Degradation of the Alzheimer's Amyloid β Peptide by Endothelin-converting Enzyme

Eckman

Reed

Eckman

2001

Journal of Biological Chemistry

317

245

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Deposition of ␤-amyloid (A␤) peptides in the brain is an early and invariant feature of all forms of Alzheimer's disease. As with any secreted protein, the extracellular concentration of A␤ is determined not only by its production but also by its catabolism. A major focus of Alzheimer's research has been the elucidation of the mechanisms responsible for the generation of A␤. Much less, however, is known about the mechanisms responsible for A␤ removal in the brain. In this report, we describe the identification of endothelin-converting enzyme-1 (ECE-1) as a novel A␤-degrading enzyme. We show that treatment of endogenous ECE-expressing cell lines with the metalloprotease inhibitor phosphoramidon causes a 2-3-fold elevation in extracellular A␤ concentration that appears to be due to inhibition of intracellular A␤ degradation. Furthermore, we show that overexpression of ECE-1 in Chinese hamster ovary cells, which lack endogenous ECE activity, reduces extracellular A␤ concentration by up to 90% and that this effect is completely reversed by treatment of the cells with phosphoramidon. Finally, we show that recombinant soluble ECE-1 is capable of hydrolyzing synthetic A␤40 and A␤42 in vitro at multiple sites.

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“…Second, SM-19712 caused markedly sustained ERK2 activation, whereas overexpression of ECE-1c attenuated ERK2 activation. A second ECE-1 inhibitor, PD-069185, also caused prolonged ERK2 activation, although the effect was less pronounced, probably because PD-069185 is not membrane permeant (19), whereas SM-19712 is a membrane permeable inhibitor (29). Third, the H ϩ -ATPase inhibitor bafilomycin A 1 , which prevents endosomal acidification and inhibits ECE-1-dependent SP degradation in endosomes (13), also caused sustained ERK activation.…”

Section: Ece-1 Degrades Sp In Endosomes Andmentioning

confidence: 99%

“…To confirm the effects of SM-19712, we used another ECE-1 inhibitor, PD-069185 (19). First, we examined whether PD-069185, like SM-19712 (13), inhibits resensitization of NK 1 R signaling, which is because of endosomal retention of NK 1 R. HEK-NK 1 R cells were treated with vehicle or PD-069185, challenged with SP (10 nM, 0 -10 min), washed, and incubated in SP-free medium (120 min).…”

Section: Ece-1 Regulates the Duration And Subcellular Location Of Sp-mentioning

confidence: 99%

Endosomal Endothelin-converting Enzyme-1

Cottrell

Padilla

Amadesi

et al. 2009

Journal of Biological Chemistry

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Neuropeptide signaling at the cell surface is regulated by metalloendopeptidases, which degrade peptides in the extracellular fluid, and ␤-arrestins, which interact with G protein-coupled receptors (GPCRs) to mediate desensitization. ␤-Arrestins also recruit GPCRs and mitogen-activated protein kinases to endosomes to allow internalized receptors to continue signaling, but the mechanisms regulating endosomal signaling are unknown. We report that endothelin-converting enzyme-1 (ECE-1) degrades substance P (SP) in early endosomes of epithelial cells and neurons to destabilize the endosomal mitogen-activated protein kinase signalosome and terminate signaling. ECE-1 inhibition caused endosomal retention of the SP neurokinin 1 receptor, ␤-arrestins, and Src, resulting in markedly sustained ERK2 activation in the cytosol and nucleus, whereas ECE-1 overexpression attenuated ERK2 activation. ECE-1 inhibition also enhanced SP-induced expression and phosphorylation of the nuclear death receptor Nur77, resulting in cell death. Thus, endosomal ECE-1 attenuates ERK2-mediated SP signaling in the nucleus to prevent cell death. We propose that agonist availability in endosomes, here regulated by ECE-1, controls ␤-arrestin-dependent signaling of endocytosed GPCRs.Signal transduction at the plasma membrane is tightly regulated by well characterized mechanisms. For the large family of G protein-coupled receptors (GPCRs), 2 regulation of extracellular agonist concentration and receptor coupling to heterotrimeric G proteins control signal transduction. Cell-surface metalloendopeptidases, exemplified by neprilysin, degrade neuropeptides in the extracellular fluid to regulate receptor activation (1, 2). G protein receptor kinases phosphorylate activated GPCRs to promote their interaction with ␤-arrestins, which uncouple receptors from G proteins and mediate desensitization (3). However, activated GPCRs internalize, and endocytosed receptors continue to signal by G protein-independent mechanisms. ␤-Arrestins mediate endocytosis and intracellular signaling of GPCRs. ␤-Arrestins couple GPCRs to clathrin and AP2 to mediate endocytosis (4, 5) and are scaffolds that recruit Src, Raf-1, and mitogen-activated protein kinases (MAPKs) to GPCRs in endosomes forming a MAPK signalosome, which determines the location and function of activated extracellular signal-regulated kinases (ERKs) (6 -9). Compared with our understanding of receptor regulation at the plasma membrane, little is known about the mechanisms that regulate GPCR signaling and trafficking at the endosomal membrane. Specifically, it is not known whether agonist interaction with GPCRs or GPCR interaction with ␤-arrestins is necessary for receptor signaling in endosomes. Regulation of these interactions could determine the duration of ␤-arrestin-mediated ERK activation, with important functional implications (10, 11). We hypothesized that mechanisms that regulate GPCRs at the plasma membrane also control receptor signaling and trafficking at the endosomal membrane. We recently reported t...

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Novel Selective Quinazoline Inhibitors of Endothelin Converting Enzyme-1

Cited by 45 publications

References 42 publications

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Degradation of the Alzheimer's Amyloid β Peptide by Endothelin-converting Enzyme

Endosomal Endothelin-converting Enzyme-1

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