Angiotensin-Converting Enzyme and Neutral Endopeptidase

Combined Angiotensin-Converting Enzyme and Neutral Endopeptidase 

Flynn et al. at Marion Merrell Dow Research Institute began their search for a combined ACE/NEP inhibitor by investigating derivatives of their tricyclic phenylalanylleucine (Phe-Leu) mimetic (17). This mimetic had been 

Examples of the use of molecular modeling to design a combined ACE/NEP inhibitor using known, nonpeptide inhibitors of the individual enzymes are also available. 

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Robl JA, Sun C-Q et al (1997) Dual metalloprotease inhibitors mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 40 1570-1577... 

JA Robl, C Sun, J Stevenson, DE Ryono, LM Simpkins, MAP Cimarusti, T Dejneka, WA Slusarchyk, S Chao, L Stratton, RN Misra, MS Bednarz, MM Asaad, HS Cheung, BE Aboa-Offei, PL Smith, PD Mathers, M Fox, TR Schaeffer, AA Seymour, NC Trippodo. Dual metalloprotease inhibitors mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 40 1570-1577, 1997. 

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. 

IV. ANGIOTENSIN CONVERTING ENZYME (ACE) AND NEUTRAL ENDOPEPTIDASE INHIBITORS... 

Christensen S, Shalmi M, Hansen AK, Marcussen N (1997) Effects of pepindopril and hydrochlorothiazide on the longterm progression of lithium-induced chronic renal failure in rats. Pharmacol Toxicol 80 132-141 Cohen DS, Mathis JE, Dotson RA et al. (1998) Protective effects of CGS 30440, a combined angiotensin-converting enzyme inhibitor and neutral endopeptidase inhibitor, in a model of chronic renal failure. J Cardiovasc Pharmacol 32 87-95... 

Table 2. Pairwise comparison of the topology and sequence of members of the long spacer family. Primary sequences for human Angiotensin Converting Enzyme [57], Botulinum Neurotoxin A [58], human Neutral Endopeptidase [59] have been used in the pairwise sequence comparison. Legend as in Table 1.

The reversal of the peptidic functional groups is often used in peptide chemistry. The obtained retropeptides are generally more resistant to enzymatic attacks (Figure For thiorphan and rctro-thiorphan an identical binding mode to the zinc protease thermolysin was demonstrated. Similar inhibition values for thermolysin and neutral endopeptidase were observed, whereas, for another zinc protease, angiotensin-converting enzyme (ACE), noticeable differences for inhibition were found (Figure 15.47). 

Mixanpril, N-[(2S,3 R)-2-benzoylthiometh-yl-3-phenylbutanoyl]-L-alanine, a dual inhibitor for the neutral endopeptidase-24.11 (NEP) and the angiotensin-converting enzyme (ACE). The orally administerable mixanpril is important for the treatment of high blood pressure and cardiac defects [S. Turcaud et al., Bioorg. Med. Chem. Lett. 1995, 5, 1893]. 

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