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Details

Stereochemistry ABSOLUTE
Molecular Formula C29H41NO7
Molecular Weight 515.6383
Optical Activity UNSPECIFIED
Defined Stereocenters 3 / 3
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of CANDOXATRIL

SMILES

COCCOC[C@H](CC1(CCCC1)C(=O)N[C@H]2CC[C@H](CC2)C(O)=O)C(=O)OC3=CC=C4CCCC4=C3

InChI

InChIKey=ZTWZVMIYIIVABD-OEMFJLHTSA-N
InChI=1S/C29H41NO7/c1-35-15-16-36-19-23(27(33)37-25-12-9-20-5-4-6-22(20)17-25)18-29(13-2-3-14-29)28(34)30-24-10-7-21(8-11-24)26(31)32/h9,12,17,21,23-24H,2-8,10-11,13-16,18-19H2,1H3,(H,30,34)(H,31,32)/t21-,23-,24+/m0/s1

HIDE SMILES / InChI

Description

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

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
7.8 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

PubMed

Patents

Sample Use Guides

In Vivo Use Guide
200 mg candoxatril capsules twice daily.
Route of Administration: Oral
In Vitro Use Guide
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.