Neutral endopeptidase inhibitors

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. 

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. 

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. 

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... 

ANP is a polypeptide hormone that is secreted in large quantities by the atrial portion of the heart and from a variety of other mammalian cell types. It exerts many of its actions via activation of particulate guanylate cyclase [16, 134]. ANP is present in human follicular fluids [163] and specific ANP receptors have been identified in human spermatozoa [144]. Sperm chemotaxis to ANP was demonstrated by sperm accumulation in capillaries with ascending [6] and descending [192] gradients and by choice assays [192] (Table 4). It is not yet known whether ANP is involved in sperm chemotaxis in vivo and whether the physiological chemoattractant for human spermatozoa is an ANP-like substance. Since chemotaxis to ANP at physiological concentrations can be observed only in the presence of a neutral endopeptidase inhibitor such... 

Ru(cod)(Me-allyl)2 was employed as precursor by Chirotech [23] for the hydrogenation of the a,(3-unsaturated ester shown in Scheme 42, an intermediate for candoxatril, a neutral endopeptidase inhibitor. The hydrogenation was also carried out on a 250-kg scale by PPG-Sipsy [97] with a Ru/MeO-biphep complex. Merck [98] developed a pilot process using a Ru/josiphos complex for the very difficult reductimi of a tetrasubstituted C=C bond to produce the renin inhibitor... 

Thompson JS, Sheedy W, Morice AH. Effects of the neutral endopeptidase inhibitor, SCH 42495, on the cardiovascular remodelling secondary to chronic hypoxia in rats. 

Bloch, M.(. and Basile, J.N. (2010) Combination angiotensin receptor blocker-neutral endopeptidase inhibitor provides additive blood pressure reduction over angiotensin receptor blocker alone. J. Clin. Hypertens., 12, 809-812. 

Meng X, Maggs JL, Pryde DC, Planken S, Jenkins RE, Peak-man TM, Beaumont K, Kohl C, Park BK, Stachulski AV. Cyclization of the acyl glucuronide metabolite of a neutral endopeptidase inhibitor to an electrophilic glutarimide synthesis, reactivity, and mechanistic analysis. J. Med. Chem. 2007 50 6165-6176. 

McDowell G, Nicholls DP. The therapeutic potential of can-doxatril, a neutral endopeptidase inhibitor, in humans Cardi-ovasc. Drug Rev. 2000 18(4) 259 270. 

Bevan EG, Connell JM, Doyle J, Carmichael HA, Davies DL, Lorimer AR, Mclnnes GT. Candoxatril, a neutral endopeptidase inhibitor efficacy and tolerability in essential hypertension. J. Hypertens. 1992 10(7) 607 13. 

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