Endopeptidase inhibitor

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)... 

Tabrizchi R. Dual ACE and neutral endopeptidase inhibitors. Drugs 2003 63 2185-202. 

The endogenous hormone atrial natriuretic peptide (ANP), which acts to increase blood pressure, is, like many other effector peptides, excised from a longer native chain by an endopeptidase enzyme, that is, an agent that cleaves bonds well along the chain of amino acids. A small-molecule endopeptidase inhibitor lowers blood pressure by inhibiting the release of ANP. The inhibitor candoxatril (6-8) is now... 

Atrial Natriuretic Peptide Potentiator Diuretics. Neural endopeptidase inhibitors or atrial peptidase inhibitors are compounds that inhibit the enzyme (hat degrades ANP. resulting in higher plasma concemratioas, and longer duration of action, of ANP. The diuretic effects of this class... 

Isocyanides, formal divalent carbon functionalities, are ideal candidates for the development of MCRs. Their reaction with carbonyls and imines, through an a-addition process, generates a zwitterionic intermediate, which is then trapped by a nucleophile. The resulting double a-addition adduct is unstable and rapidly undergoes the Mumm rearrangement to afford the final product (Scheme 12.32). The venerable three-component Passerini reaction is the first MCR based on this type of reaction process [116]. It addresses the formation of a-acyloxycarboxamides, which constitute a class of very versatile synthons in organic chemistry. In the present context, this reaction was utilized by Schmidt and collaborators for the elaboration of intermediate 234 [117], a key fragment for the synthesis of the prolyl endopeptidase inhibitor Eurystatin A 231 (Scheme 12.33) [118]. 

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

The S -(-)-a-[(acetylthio)methyl]phenylpropionic acid (21) is a key chiral intermediate for the neutral endopeptidase inhibitor (22) [48], We [44] have demonstrated the lipase-catalyzed stereoselective hydrolysis of thioester bond of racemic a-[(acetylthio)methyl]phenylpropionic acid (21) in organic solvent to yield A-(+)-a-[(mercapto)methyl]phenylpropionic acid (23) and Y-(-)-(21). Using lipase PS-30, the Y-(-)-(21) was obtained in 40% reaction yield (theoretical max. 50%) and 98% e.e. (Fig. 9). 

Figure 9 Preparation of chiral synthon for neutral endopeptidase inhibitor stereoselective enzymatic hydrolysis of racemic ot-[(acetylthio)methyl]phenylpropionic acid (21).

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... 

Neutral endopeptidase inhibitors. Nitric oxide donors, Endothelin receptor antagonists... 

Cheung, D., Bel, E.H., Den Hartigh, J. etal. (1992). The effect of an inhaled neutral endopeptidase inhibitor, thiorphan, on airway responses to neurokinin A in normal humans in vivo. Am. Rev. Respir. Dis. 145, 1275-1280. 

Kohrogj, H., Graf, P.D., Sekizawa, K. etal. (1988). Neutral endopeptidase inhibitors potentiate substance P- and capsaicin-induced cough in awake guinea-pigs. J. Clin. Invest. 82, 2063-2068. 

Owens, T. D., Araldi, G. L., Nutt, R. F., Semple, J. E. Concise total synthesis of the prolyl endopeptidase inhibitor eurystatin A via a novel Passerini reaction-deprotection-acyl migration strategy. Tetrahedron Lett. 2001,42, 6271-6274. 

Encron rizolipasc. endogenous pyrogen > interleukin-1. ENDOPEPTIDASE INHIBITORS act at one or other of the endopeptidase enzymes that cleave the C-terminal residue from oligopeptides or proteins (thus are stricdy proteinases). They can be divided into classes on the basis of their functional characteristics. These classes are dealt with separately in terms of their alternate names, notable substrates and inhibitors. They often act along with ectopeptidases - the carboxypeptidases and amino-peptidases. Endopeptidase inhibitors contain members of the metalloproteinase and serine protease families. Some are important neuropeptidases - concerned with degradation of... 

Inhibitors include thiorphan, phosphoramidon and SCH 32615, See neutral endopeptidase inhibitors. 

REDUCTASE INHIBITORS DOPA-DECARBOXYLASE INHIBITORS DOPAMINE P-HYDROXYLASE INHIBITORS ENDOPEPTIDASE INHIBITORS HMG-COA REDUCTASE INHIBITORS NEUTRAL ENDOPEPTIDASE INHIBITORS NITRIC OXIDE SYNTHASE INHIBITORS PHOSPHOLIPASE INHIBITORS 5a-REDUCTASE INHIBITORS REVERSE TRANSCRIPTASE INHIBITORS THROMBOXANE SYNTHASE... 

Other members of the metalloprotease family cleave oligopeptides (arbitrarily defined as having less than 50 amino acid residues) and do not necessarily act on proteins. These include a number of neuropeptidases of special interest and a number are discussed elsewhere. See ACE inhibitors aminopeptidase inhibitors carboxypeptidase inhibitors endopeptidase inhibitors neutral endopeptidase inhibitors. 

Salyrgan mercuderamide. sampatrilat [ban, inn] is a pseudopeptide, an ace INHIBITOR and neutral ENDOPEPTIDASE INHIBITOR ( enkephalinase inhibitor). It is a VASODILATOR and ANTIHYPERTENSIVE. 

SQ 29072 is a mercapto compound, a NEUTRAL ENDOPEPTIDASE INHIBITOR. It enhances the antihypertensive activity of ACE inhibitors. 

R635 K. Kanai, M. Feher, A. Lopata, B. Podanyi, I. Novik, E. Susan, I. Hermecz and P. Aranyi, Molecular Modeling and CoMFA Studies on Prolyl Endopeptidase Inhibitors , Acta Pharm. Hung., 1999, 69, 240 R636 L. Toke, Supramolecular Chemistry, Crown Ethers , Magy. Kem. Foly., 2000,106, 111... 

Takahama K, Fuchikami J, Kai H, Isohama Y, Miyata T (1995) Inhalation of phosphoramidon, a neutral endopeptidase inhibitor, induces cough in awake guinea-pigs. Arch Int Pharmacodyn Ther 330 241-250... 

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