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Chemical Compound Review

candoxatrilat     4-[[1-[2-carboxy-3-(2- methoxyethoxy)propyl...

Synonyms: SureCN389958, SureCN389959, UK-69578, UK-73967, LS-172580, ...
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Disease relevance of candoxatrilat

  • The purpose of this study was the assessment of kidney neutral endopeptidase expression and responses to candoxatrilat (a specific inhibitor of this enzyme) in rats with CCl4-induced cirrhosis [1].
  • Three groups of cirrhotic rats with ascites (n = 10) received vehicle alone or 3 or 10 mg/kg candoxatrilat [1].
  • 1. The present studies compare the early renal response to (a) an endopeptidase-24.11 (E-24.11) inhibitor (candoxatrilat) (b) an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) and (c) the combination of endopeptidase-24.11 and ACE inhibition in the rat A-V fistula model of chronic volume overload [2].

Psychiatry related information on candoxatrilat


High impact information on candoxatrilat


Biological context of candoxatrilat

  • CONCLUSIONS: Candoxatrilat has few effects on systemic hemodynamics and hormonal status; its portal hypotensive action depends on effects exerted on intrahepatic vascular resistance [9].
  • Candoxatrilat (10 mg/kg) also reduced tubular solute-free water reabsorption (P < 0.03) in cirrhotic rats, but renal blood flow, arterial pressure, and plasma renin activity were unaffected [1].
  • In Candoxatrilat-treated collared arteries, vasorelaxation to acetylcholine was improved, along with reductions in PAI-1 levels, macrophage numbers and intimal area (all p < 0.05) [10].
  • 3. Candoxatrilat (3 mg kg-1) alone had no significant effect on sodium excretion or blood pressure but markedly potentiated the natriuretic response to BNP [11].
  • In nephrectomized rats, the pharmacokinetics of 125I-ANF and the changes induced by candoxatrilat were similar to those observed in intact animals, whilst the effects of C-ANF4-23 alone were greater than in intact animals [12].

Anatomical context of candoxatrilat


Associations of candoxatrilat with other chemical compounds

  • Combining enalapril pretreatment with candoxatrilat significantly attenuated the increments in absolute and fractional sodium excretions in response to the neutral endopeptidase inhibitor [7].
  • METHODS: Twelve male stable cyclosporine-treated renal transplant recipients received a single 100-mg i.v. dose of the neutral endopeptidase EC 24.11 inhibitor candoxatrilat in a double-blind, placebo-controlled cross-over study [15].
  • In cirrhotic rats, Western blot analysis revealed a 170% increase in renal neutral endopeptidase protein content (P < 0.03), mainly in the proximal nephron and macula densa, and both candoxatrilat dosages increased plasma ANP levels, urinary volume, and urinary excretion of sodium, ANP, and cGMP compared with vehicle alone (all P < 0.03) [1].
  • (+/-) candoxatrilat reduces the clearance of both 125IANF and ANF 5-28, and prolongs the elimination half-life [16].
  • Salt supplements enhanced the diuretic, natriuretic and ANP responses to 0.3 nmol/kg intravenous of hANP 99-126 in monkeys treated with vehicle or 10 mumol/kg intravenous of candoxatrilat [17].

Gene context of candoxatrilat

  • After candoxatrilat plasma ANF rose two- to threefold from baseline, and remained elevated for 5(N) and 7(M,S) hours (P < 0.01(N,S), P < 0.03(M)) associated with an immediate rise in urine cGMP excretion from 23.5(N), 25.4(M) and 10.4(S) nmol/hr (base) to 51.7(N), 73.8(M) and 27.5(S)(peak) lasting 7(N,M,S) hours (P < 0.01(N,M,S)) [18].
  • UK-69,578 increases endogenous ANF levels and produces natriuretic and diuretic responses intravenously in mice [19].
  • A search for potent inhibitors of EC, an enzyme which is found most abundantly in the kidney and which degrades atrial natriuretic factor, has led to the identification of UK-69,578 [19].
  • 4. Similarly SC 46542 (68 micrograms kg-1; 6.8 micrograms kg-1 min-1) which produced no significant effect on its own, potentiated the natriuresis-induced by BNP, although the effect was of shorter duration compared to that of candoxatrilat [11].
  • The combination of C-ANF4-23 and candoxatrilat again produced a substantial increase in T1/2 beta (153%) and decreases in Vd (55%) and Clp (78%) in nephrectomized animals, although these changes could not be distinguished from those seen in intact animals treated with the same combination [12].

Analytical, diagnostic and therapeutic context of candoxatrilat


  1. Overexpression of kidney neutral endopeptidase (EC and renal function in experimental cirrhosis. Sansoè, G., Aragno, M., Mastrocola, R., Cutrin, J.C., Silvano, S., Mengozzi, G., Smedile, A., Rosina, F., Danni, O., Rizzetto, M. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  2. Renal effects of concurrent E-24.11 and ACE inhibition in the aorto-venocaval fistula rat. Kirk, J.E., Wilkins, M.R. Br. J. Pharmacol. (1996) [Pubmed]
  3. Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Pryde, D.C., Cook, A.S., Burring, D.J., Jones, L.H., Foll, S., Platts, M.Y., Sanderson, V., Corless, M., Stobie, A., Middleton, D.S., Foster, L., Barker, L., Van Der Graaf, P., Stacey, P., Kohl, C., Coggon, S., Beaumont, K. Bioorg. Med. Chem. (2007) [Pubmed]
  4. Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo. Ferro, C.J., Spratt, J.C., Haynes, W.G., Webb, D.J. Circulation (1998) [Pubmed]
  5. Neurohormonal inhibition and hemodynamic unloading during prolonged inhibition of ANF degradation in patients with severe chronic heart failure. Münzel, T., Kurz, S., Holtz, J., Busse, R., Steinhauer, H., Just, H., Drexler, H. Circulation (1992) [Pubmed]
  6. Renal response to candoxatrilat in patients with heart failure. Good, J.M., Peters, M., Wilkins, M., Jackson, N., Oakley, C.M., Cleland, J.G. J. Am. Coll. Cardiol. (1995) [Pubmed]
  7. Natriuretic response to neutral endopeptidase inhibition is blunted by enalapril in healthy men. Motwani, J.G., Lang, C.C., Cramb, G., Struthers, A.D. Hypertension (1995) [Pubmed]
  8. Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides. Pryde, D.C., Maw, G.N., Planken, S., Platts, M.Y., Sanderson, V., Corless, M., Stobie, A., Barber, C.G., Russell, R., Foster, L., Barker, L., Wayman, C., Van Der Graaf, P., Stacey, P., Morren, D., Kohl, C., Beaumont, K., Coggon, S., Tute, M. J. Med. Chem. (2006) [Pubmed]
  9. Neutral endopeptidase (EC in cirrhotic liver: a new target to treat portal hypertension? Sansoè, G., Aragno, M., Mastrocola, R., Restivo, F., Mengozzi, G., Smedile, A., Rosina, F., Danni, O., Parola, M., Rizzetto, M. J. Hepatol. (2005) [Pubmed]
  10. Vascular neutral endopeptidase inhibition improves endothelial function and reduces intimal hyperplasia. Barber, M.N., Kanagasundaram, M., Anderson, C.R., Burrell, L.M., Woods, R.L. Cardiovasc. Res. (2006) [Pubmed]
  11. Effect of endopeptidase-24.11 inhibition and of atrial natriuretic peptide clearance receptor ligand on the response to rat brain natriuretic peptide in the conscious rat. Kirk, J.E., Wilkins, M.R. Br. J. Pharmacol. (1993) [Pubmed]
  12. The pharmacokinetics of 125I-atrial natriuretic factor in anaesthetized rats. Effects of neutral endopeptidase inhibition with candoxatrilat and of ANF-C receptor blockade. Barclay, P.L., Bennett, J.A., Greengrass, P.M., Griffin, A., Samuels, G.M., Shepperson, N.B. Biochem. Pharmacol. (1992) [Pubmed]
  13. Regulation of secretion and clearance of C-type natriuretic peptide in the interaction of vascular endothelial cells and smooth muscle cells. Komatsu, Y., Itoh, H., Suga, S., Igaki, T., Ogawa, Y., Kishimoto, I., Nakagawa, O., Yoshimasa, T., Nakao, K. J. Hypertens. (1996) [Pubmed]
  14. Inhibition of the metabolism of atrial natriuretic factor causes diuresis and natriuresis in chronic heart failure. Northridge, D.B., Jardine, A.G., Findlay, I.N., Archibald, M., Dilly, S.G., Dargie, H.J. Am. J. Hypertens. (1990) [Pubmed]
  15. Acute reversal of cyclosporine nephrotoxicity by neutral endopeptidase inhibition in stable renal transplant recipients. Lipkin, G.W., Thuraisingham, R., Dawnay, A.B., Harwood, S.M., Raine, A.E. Transplantation (1997) [Pubmed]
  16. The atriopeptidase inhibitor (+/-) candoxatrilat reduces the clearance of atrial natriuretic factor in both intact and nephrectomized rats: evidence for an extrarenal site of action. Barclay, P.L., Bennett, J.A., Samuels, G.M., Shepperson, N.B. Biochem. Pharmacol. (1991) [Pubmed]
  17. Sodium loads enhance the natriuretic responses to atrial natriuretic peptide and neutral endopeptidase inhibitors in conscious cynomolgus monkeys. Seymour, A.A., Asaad, M.M., Abboa-Offei, B., Smith, P.L., Rogers, W.L. Clin. Exp. Pharmacol. Physiol. (1994) [Pubmed]
  18. Enhanced natriuretic response to neutral endopeptidase inhibition in patients with moderate chronic renal failure. Lipkin, G.W., Dawnay, A.B., Harwood, S.M., Cattell, W.R., Raine, A.E. Kidney Int. (1997) [Pubmed]
  19. UK-69,578, a novel inhibitor of EC which increases endogenous ANF levels and is natriuretic and diuretic. Danilewicz, J.C., Barclay, P.L., Barnish, I.T., Brown, D., Campbell, S.F., James, K., Samuels, G.M., Terrett, N.K., Wythes, M.J. Biochem. Biophys. Res. Commun. (1989) [Pubmed]
  20. Increased circulating atrial natriuretic factor concentrations in patients with chronic heart failure after inhibition of neutral endopeptidase: effects on diastolic function. Northridge, D.B., Jardine, A., Henderson, E., Dilly, S.G., Dargie, H.J. British heart journal. (1992) [Pubmed]
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