Endothelin-converting enzyme inhibitor

Systemic administration of endothelin receptor antagonists or endothelin-converting enzyme inhibitors causes vasodilation and decreases arterial pressure in humans and experimental animals. Intra-arterial administration of the drugs also causes slow-onset forearm vasodilation in humans. These observations provide evidence that the endothelin system participates in the regulation of vascular tone, even under resting conditions. The activity of the system is higher in males than in females. It increases with age, an effect that can be counteracted by regular aerobic exercise. 

In the total synthesis of ( )-WS75644B 360, a biaryl endothelin converting enzyme inhibitor, pyrone 357 derived from kojic acid was converted to pyridone 358 by reaction with concentrated ammonium hydroxide in a sealed flask at 90 °C. The resulting pyridine was subsequently converted to 2,4,5-trisubstituted pyridine 359 and ultimately elaborated to complete the total synthesis (Scheme 54) <1997TL1297>. 

Lloyd, J., Schmidt, J.B., Hunt, J.T., Banish, J.C., Little, D.K. and TVmiak, A.A., Solid phase synthesis of phosphinic acid endothelin converting enzyme inhibitors, Bioorg. Med. Chem. Lett., 6 (1996) 1323-1326. 

The formation of endothelins can be blocked by inhibiting endothelin-converting enzyme with phosphoramidon. Phosphoramidon is not specific for endothelin-converting enzyme, but several more selective inhibitors are now available for research. Although the therapeutic potential of these drugs appeared similar to that of the endothelin receptor antagonists (see below), their use has been eclipsed by endothelin antagonists. 

Angiotensin I converting enzyme Acquired immunodeficiency syndrome Aspartic protease inhibitor Bowman Birk protease inhibitor protein Chymotrypsin Cysteine protease inhibitor Endothelin-converting enzyme Elastase... 

The use of specific quenched fluorescent substrates (QFS) provides a rapid and sensitive method to measure peptidase activity, and is readily adaptable to high-throughput screening of potential peptidase inhibitors. In this chapter, we discuss general considerations for the development of QFS assays, and describe in detail an assay protocol for the mammalian metallopeptidase, endothelin-converting enzyme. 

The work carried out to isolate and identify the pharmacologically important ECE has characterized the enzymes as metalloproteases because of their inhibition by the known metalloprotease inhibitor phosphoramidon (6). Many groups have published data on the use of phosphoramidon in their enzyme systems. A patent application for phosphoramidon and its close analogues for use as an endoserine - (endothelin) - converting enzyme... 

Doggrell SA. The therapeutic potential of endothelin-1 receptor antagonists and endothehn-converting enzyme inhibitors on the cardiovascular system. Expert Opin Investig Drugs 2002 ll(ll) 1537-52. 

Endothelin converting enzyme (ECE) has yet to be fully characterized. It is a membrane-located enzyme found in the vascular endothelium. It is essential in the production of endothelin in the body since it converts the inactive precursor big ET-1 to endothelin-1. It is an unusual enzyme because it cleaves at a Tyr-Val link. Like endopeptidase-24.11, it is inhibited by phosphoramidon (so is a metalloproteinase), and these two enzymes are often colocated. Furthermore, monoclonal antibody co-precipitation studies indicate they share a common epitope, and a homology to the extent of about 39%, ECE is also similar to the bacterial metalloprotease thermolysin, but is more specific. If a specific inhibitor is discovered that can act in vivo, then clearly such a drug could modulate endothelin production throughout the body, which would have important consequences (e.g. in antihypertensive therapy). 

Two distinct phosphorus structures, 373 and 374, are reported to be potent inhibitors of endothelin-converting enzyme and neutral endopeptidase. The latter compound is also a potent inhibitor of angiotensin-converting enzyme. 

Endothelin converting enzyme (ECE) inhibitors have been shown to be useful... 

Wallace et alP in a series of inhibitors of endothelin-converting enzyme (ECE-1) derived from the biphenyl compound CGS 26 303 and its analogues. ... 

De Lombaert, S., Stamford, L.B., Blanchard, L., Tan, J., Hoyer, D., et al. (1997) Potent non-peptidic dual inhibitors of endothelin-converting enzyme and neutral endopeptidase. 22.11. Bioorg. Med. Chem. Lett. 8 1059-1064. 

C23H34N3O10P, Mr 543.51, mp. of Na salt 173-178 °C (decomp.). An antibiotic from cultures of 5(/iepw/nyces tanashiensis and other actinomycetes. P. is an inhibitor of thermolysin, encephalinase, and endothelin converting enzyme. It inhibits the spontaneous metastasis of certain tumor cells. P. is related to talopeptin, a metalloproteinase inhibitor. For total synthesis, see Lit.. ... 

WS7S624-A and B. Endothelin-converting enzyme (ECE) inhibitors from fermentation broths of Saccha-rothrix sp. no. 75624. ECE inhibitors are a new therapeutic principle for therapy of cardiac insufficiency, kidney failure and other circulatory diseases. W. belong to the few non-peptidic small molecules with this effect, IC50 (W. B) 30 ng/mL. 

WS75624B (123) is an endothelin-converting enzyme (ECE) inhibitor that is potentially useful in the treatment of hypertension. Stannane 120 reacting with iodide 121 afforded 122 which was further elaborated into 123. 

Angucycline antibiotic. Prod, by Streptosporangium roseum. Inhibitor of endothelin converting enzyme. 

Phosphoramidon (33), an inhibitor of the endothelin-converting enzyme, and the glycosylated phosphatidylcholines 34, which are closely related to a newly dicovered, natural fungicide, have been synthesized by use of the phosphorodi-chloridate method. 

Bach, T. and Heuser, S. (2002) Total synthesis of the naturally occurring endothelin converting enzyme (ECE) inhibitor WS 75624 A. Synlett, (12), 2089-2091. 

Inhibitors of ECE (endothelin-converting enzyme) create a hypotensive effect by reducing the production of endothelins. 

Patil, A.D., Freyer, A.J., Breen, A., Carte, B., and Johnson, R.K. (1996a) Halistanol disulfate B, a novel sulfated sterol from the sponge Pachastrella sp. inhibitor of endothelin converting enzyme. J. Nat. Prod., 59, 606-608. 

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