Endothelin converting enzyme inhibition

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. 

Some QFS compounds are difficult to solubilize at high concentration in aqueous solution. Dissolving in DMSO or ethanol can circumvent this, but care must be taken as these solvents may interfere with enzyme activity. For example, we have determined that final concentrations of DMSO or ethanol above 2% significantly inhibit endothelin converting enzyme activity. 

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... 

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). 

Manzamines exhibit potent cytotoxicity (Table 1). Manzamine A (32) and its 8-hydroxy (33) and 8-methoxy derivatives are active against this HSV-II (IC50 0.05, 0.1 and 0.1 pg/mL, respectively) (48). Manzamine C (35) is an inducer of EL-4.IL-2, which is a measure of perturbation of signal transduction (204). Ircinol A (119) showed inhibition against endothelin converting enzyme (IC50 5 5 pg/mL) (91). 

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.. ... 

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