Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C20H33NO7 |
Molecular Weight | 399.4785 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 3 / 3 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
COCCOC[C@H](CC1(CCCC1)C(=O)N[C@H]2CC[C@H](CC2)C(O)=O)C(O)=O
InChI
InChIKey=ACZWIDANLCXHBM-HRCADAONSA-N
InChI=1S/C20H33NO7/c1-27-10-11-28-13-15(18(24)25)12-20(8-2-3-9-20)19(26)21-16-6-4-14(5-7-16)17(22)23/h14-16H,2-13H2,1H3,(H,21,26)(H,22,23)(H,24,25)/t14-,15-,16+/m0/s1
Molecular Formula | C20H33NO7 |
Molecular Weight | 399.4785 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 3 / 3 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
DescriptionSources: https://www.drugbank.ca/drugs/DB00616Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/1315825 | https://www.ncbi.nlm.nih.gov/pubmed/10937982 | https://www.ncbi.nlm.nih.gov/pubmed/21515054 | https://www.ncbi.nlm.nih.gov/pubmed/2529858 | https://www.ncbi.nlm.nih.gov/pubmed/26082640
Sources: https://www.drugbank.ca/drugs/DB00616
Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/1315825 | https://www.ncbi.nlm.nih.gov/pubmed/10937982 | https://www.ncbi.nlm.nih.gov/pubmed/21515054 | https://www.ncbi.nlm.nih.gov/pubmed/2529858 | https://www.ncbi.nlm.nih.gov/pubmed/26082640
Candoxatril is the orally-active prodrug of candoxatrilat (UK-73967), a potent neutral endopeptidase (NEP) inhibitor. Neutral endopeptidase inhibitors such as Candoxatril have a dual mechanism of action. They inhibit two metalloprotease enzymes, neutral endopeptidase, and ACE, resulting in an increased availability of natriuretic peptides that exhibit vasodilatory effects and, possibly, tissue protective effects. Candoxatril is the first drug of its kind to be released for clinical trials regarding heart failure. This is because Candoxatril produces favorable hemodynamic effects in patients with chronic heart failure. It has been demonstrated that Candoxatril is associated with a beneficial hemodynamic effect that is useful both for rest and exercise. In several different studies, candoxatril has been shown to improve performance in people with heart failure. In one study, 12 different patients were selected, all with moderately severe heart failure. On day one of this study, the candoxatril had increased plasma ANP levels, suppressed aldosterone and decreased right atrial and pulmonary capillary wedge pressures. After treatment for 10 days, patients health had improved with an increase of basal ANP and a decrease of aldosterone, along with a reduced body weight that could be a reflection of chronic natriuretic, diuretic effects, or both. It was decided that on day 10 of the study, the effects of candoxatril were similar to that on day one.
Originator
Sources: https://www.ncbi.nlm.nih.gov/pubmed/2529858
Curator's Comment: # Pfizer Central Research
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL1944 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21515054 |
7.8 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
PubMed
Title | Date | PubMed |
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Renal and hormonal effects of chronic inhibition of neutral endopeptidase (EC 3.4.24.11) in normal man. | 1993 Jul |
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Comparison of a vasopeptidase inhibitor with neutral endopeptidase and angiotensin-converting enzyme inhibitors on bradykinin metabolism in the rat coronary bed. | 2001 Apr |
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Omapatrilat, a dual angiotensin-converting enzyme and neutral endopeptidase inhibitor, prevents fatty streak deposit in apolipoprotein E-deficient mice. | 2001 Apr |
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Potentiation of urinary atrial natriuretic peptide interferes with macula densa function. | 2001 Aug 15 |
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Chronic endopeptidase inhibition in DOCA-salt hypertension: mechanism of cardiovascular protection. | 2003 Aug |
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[The new class of drugs-- metalloprotease inhibitors -- in the treatment of heart failure]. | 2004 |
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Dual inhibition of ACE and NEP provides greater cardioprotection in mice with heart failure. | 2004 Feb |
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Neutral endopeptidase 24.11 is important for the degradation of both endogenous and exogenous glucagon in anesthetized pigs. | 2004 Sep |
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Dual inhibition of angiotensin converting enzyme and neutral endopeptidase produces effective blood pressure control in spontaneously hypertensive rats. | 2005 |
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Angiotensin I-converting enzyme-dependent and neutral endopeptidase-dependent generation and degradation of angiotensin II contrarily modulate noradrenaline release: implications for vasopeptidase-inhibitor therapy? | 2005 Aug |
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Natriuretic and antialdosterone actions of chronic oral NEP inhibition during progressive congestive heart failure. | 2005 May |
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Neutral endopeptidase (EC 3.4.24.11) in cirrhotic liver: a new target to treat portal hypertension? | 2005 Nov |
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Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. | 2005 Sep |
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An expanded set of amino acid analogs for the ribosomal translation of unnatural peptides. | 2007 Oct 3 |
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Neutral endopeptidase inhibitor suppresses the early phase of atrial electrical remodeling in a canine rapid atrial pacing model. | 2008 Apr 1 |
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Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema. | 2008 Mar |
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Inhibition of neutral endopeptidase 24.11 does not potentiate the improvement in glycemic control obtained with dipeptidyl peptidase-4 inhibition in diabetic Goto-Kakizaki rats. | 2009 Nov |
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Natriuretic and renoprotective effect of chronic oral neutral endopeptidase inhibition in acute renal failure. | 2010 Jan |
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The application of fully automated on-line solid phase extraction in bioanalysis. | 2010 May 1 |
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New function for an old enzyme: NEP deficient mice develop late-onset obesity. | 2010 Sep 16 |
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Effect of Treatment of Sprague Dawley Rats with AVE7688, Enalapril, or Candoxatril on Diet-Induced Obesity. | 2011 |
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Role of the effect of inhibition of neutral endopeptidase on vascular and neural complications in streptozotocin-induced diabetic rats. | 2011 Jan 15 |
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Effect of inhibition of angiotensin converting enzyme and/or neutral endopeptidase on vascular and neural complications in high fat fed/low dose streptozotocin-diabetic rats. | 2012 Feb 29 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/10937982
200 mg candoxatril capsules twice daily.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/1443870
The acute effect of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) on pulmonary vascular tone in normoxia and acute hypoxia in the absence and presence of a specific inhibitor of neutral endopeptidase 24.11 (NEI, UK 73, 967, candoxatrilat; Pfizer) in the isolated and blood-perfused rat lung preparation was studied. Baseline pulmonary artery pressure (Ppa) was 16.4 +/- 0.3 mm Hg in lungs from normoxic control rats and 22.5 +/- 0.3 mm Hg in lungs from rats kept in hypoxia (FIO2 = 10%) for 7 days. Acute hypoxic pulmonary vasoconstriction (HPV delta Ppa) was similar in normoxic control rats (9.5 +/- 0.6 mm Hg) and chronically hypoxic rats (9.8 +/- 0.9 mm Hg). NEI at 0.07 and 0.2 mg had no effect on baseline Ppa or HPV delta Ppa. Synthetic BNP at 10 nM had no effect on baseline Ppa but produced a 2.8 +/- 0.2 mm Hg reduction in HPV delta Ppa alone and 2.7 +/- 0.2 mm Hg reduction in the presence of 0.07 mg NEI in normoxic control rats. In contrast, ANP at 10 nM produced a significantly greater decrease in HPV delta Ppa in the presence of 0.07 mg NEI (4.8 +/- 0.3 mm Hg, p < 0.05) compared with ANP alone (2.9 +/- 0.4 mm Hg), and similar results were also observed in chronically hypoxic rats.
Substance Class |
Chemical
Created
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admin
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Record UNII |
7WU8BZ90TH
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Record Status |
Validated (UNII)
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Record Version |
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C783
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m3015
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C77602
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123122-54-3
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ACTIVE MOIETY |