Neutral endopeptidases

Because renal vasodilatation and hyperfiltration are often associated with a natriuretic response, a number of activators or inhibitors of endogenous vasoactive systems can cause increased NaCl excretion, and some of these may be developed into compounds of clinical interest in special situations. Such agents include natriuretic pqDtides most notably B-type natriuretic peptide (nesiritide), neutral endopeptidase (NEP) inhibitors (thiorphan, phosphoramidon), mixed NEP and ACE inhibitors (omapatrilat), guanylin and uroguanylin, kinins, prostaglandins of the E series, adrenomedullin, relaxin, prolactin, and others. 

ECEs are metalloproteinases that are homologous to the neutral endopeptidase (NEP, E-24.11, neprilysin) unlike NEP, however, they form disulfide-bonded homodimers. In man, with ECE-1 and ECE-2, two isoforms are known, which are encoded by two separate genes. For ECE-1 four different variants have been identified (ECE-1 a-d), which are generated by the use of alternative promoters (Table 2). The ECE-1 isoforms only differ in their N-terminal amino acid sequence. For ECE-2, a single gene product has been described in... 

AHF acute heart failure, CHF chronic heart failure, CRF chronic renal failure, NEP neutral endopeptidase, ECE endothelin converting enzyme, PAH pulmonary arterial hypertension. 

ET-1 from big-ET-1 by other proteases such as neutral endopeptidase or other currently unidentified proteases. Therefore, dual inhibition of ECE and NEP might inhibit ET-l generation more efficiently, than that seen for selective ECE inhibitors. However, dual inhibiton of ECE and NEP could also increase the risk for the development of AD, as both enzyme classes are involved in the degradation of A 3 peptide. 

KELL blood group antigen is a plasma membrane protein isolated from red cells homologous to zinc-binding glycoproteins with neutral endopeptidase activity. 

Neutral endopeptidase (NEP, nephrilysin) is an enzyme that preferentially catalyzes cleavage at the amino group of hydrophobic residues of the B-chain of insulin... 

The synthesis of the CG525155 (a neutral endopeptidase inhibitor) required a Pd catalyzed Tsuji-Trost reaction as the key step following the strategy described by Johnson. Starting from the optically active allenyl amino acid methylester 91 (synthesized in several steps from 90), the seco-derivative 92 as the crucial precursor was generated in several steps in high yield. The Pd (0)... 

Dusser, D.J., Jacoby, D.B., Djokic, T.D., Borson, D.B. and Nadel J.A. (1989). Virus induces airway hyperresponsiveness to taehykinins by decreasing neutral endopeptidase. Am. Rev. Resp. Dis. 139, A352. 

Sheppard, D., Thompson, J. E., Scypinski, L., Dusser, D., Nadel, J. A. and Borson, B. (1988). Toluene di-isocyanate increases airway responsiveness to substance P and decreases airway neutral endopeptidase. J. Clin. Invest. 81, 1111-1115. 

NCF Neutrophil chemotactic factor NDGA Nordihydroguaretic acid NDP Nucleoside diphosphate Neca 5 -(N-ethyl carboxamido)-adenosine NED Nedocromil sodium NEP Neutral endopeptidase (EC 3.4.24.11)... 

Rocques, B.P., Noble, F., Dauge, V., Foumie-Zaluski, M. and Beaumont, A. (1993) Neutral endopeptidase 24.11 structure, inhibition and experimental and clinical pharmacology. Pharmacological Reviews 45, 87-146. 

A composite template for ACE inhibitors and a hypothetical model of the active site of neutral endopeptidase (NEP) have been constructed and used to guide the design of dual ACE/NEP inhibitors. However, none of the tested compounds containing two bridgehead nitrogens were found promising <1996JA8231>. 

Pfaff, J.K., et al., Neutral endopeptidase (NEP) and its role in pathological pulmonary change with inhalation exposure to JP-8 jet fuel, Toxicol. Ind. Health, 12, 93, 1996. 

Sheppard, D. et al., Toluene diisocyanate increases airway responsiveness to substance P and decreases airway neutral endopeptidase, J. Clin Invest, 81, 1111, 1988. 

Cohen AJ, Bunn PA, Franklin W, Magill-Solc C, Hartmann C, Helfrich B, Gilman L, Folkvord J, Helm K, Miller YE (1996) Neutral endopeptidase Variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux. Cancer Res 56(4) 831-839. 

Neprilysin (enkephalinase, Endopeptidase-24.11, neutral endopeptidase, NEP, EC 3.4.24.11) bears considerable resemblance to other zinc-containing metallopeptidases it is an oligopeptidase that hydrolyzes enkephalins and a range of other active peptides. Enkephalins are endogenous ligands of opiate receptors, and the prolongation of their action via inhibition of enkephalinase... 

C. Oefner, A. D Arcy, M. Hennig, F. K. Winkler, G. E. Dale, Structure of Human Neutral Endopeptidase Complexed with Phosphoramidon , Protein Data Bank ID ldmt, 1999 (H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I. N. Shindyalov, P. E. Bourne, The Protein Data Bank , Nucleic Acids Res. 2000, 28, 235-242). 

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