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Identification
NameCandoxatril
Accession NumberDB00616  (APRD00027)
Typesmall molecule
Groupsapproved
Description

Candoxatril is the orally-active prodrug of candoxatrilat (UK-73967), the active enantiomer of candoxatrilat (UK-69578), a potent neutral endopeptidase (NEP) inhibitor used in the treatment of chronic heart failure.

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand namesNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number118785-03-8
WeightAverage: 515.6383
Monoisotopic: 515.288302671
Chemical FormulaC29H41NO7
InChI KeyInChIKey=ZTWZVMIYIIVABD-OEMFJLHTSA-N
InChI
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
IUPAC Name
(1s,4s)-4-({1-[(2S)-3-(2,3-dihydro-1H-inden-5-yloxy)-2-[(2-methoxyethoxy)methyl]-3-oxopropyl]cyclopentane}amido)cyclohexane-1-carboxylic acid
SMILES
COCCOC[C@H](CC1(CCCC1)C(=O)N[C@H]1CC[C@H](CC1)C(O)=O)C(=O)OC1=CC2=C(CCC2)C=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenol Esters
Direct parentPhenol Esters
Alternative parentsIndanes; Phenol Ethers; Alkyl Aryl Ethers; Dicarboxylic Acids and Derivatives; Secondary Carboxylic Acid Amides; Carboxylic Acid Esters; Carboxylic Acids; Polyamines; Enolates
Substituentsphenol ether; alkyl aryl ether; dicarboxylic acid derivative; carboxylic acid ester; carboxamide group; secondary carboxylic acid amide; polyamine; ether; carboxylic acid derivative; enolate; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the phenol esters. These are aromatic compounds containing a benzene ring substituted by an hydroxyl group and an ester group.
Pharmacology
IndicationFor treatment of hypertension, improve exercise capacity in patients with CHF receiving angiotensin converting enzyme inhibition.
PharmacodynamicsCandoxatril is the orally-active prodrug of candoxatrilat (UK-73967), the active enantiomer of candoxatrilat (UK-69578), a potent neutral endopeptidase (NEP) inhibitor used in the treatment of chronic heart failure in man.
Mechanism of actionNeutral 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.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9142
Blood Brain Barrier + 0.8437
Caco-2 permeable - 0.6787
P-glycoprotein substrate Substrate 0.8158
P-glycoprotein inhibitor I Non-inhibitor 0.8213
P-glycoprotein inhibitor II Non-inhibitor 0.9075
Renal organic cation transporter Non-inhibitor 0.7707
CYP450 2C9 substrate Non-substrate 0.7497
CYP450 2D6 substrate Non-substrate 0.7492
CYP450 3A4 substrate Substrate 0.6952
CYP450 1A2 substrate Non-inhibitor 0.7035
CYP450 2C9 substrate Non-inhibitor 0.7548
CYP450 2D6 substrate Non-inhibitor 0.8484
CYP450 2C19 substrate Non-inhibitor 0.6641
CYP450 3A4 substrate Non-inhibitor 0.9144
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8421
Ames test Non AMES toxic 0.62
Carcinogenicity Non-carcinogens 0.9494
Biodegradation Not ready biodegradable 0.8614
Rat acute toxicity 2.5001 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9833
hERG inhibition (predictor II) Non-inhibitor 0.5652
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP3.7Not Available
Predicted Properties
PropertyValueSource
water solubility2.25e-03 g/lALOGPS
logP3.55ALOGPS
logP4.68ChemAxon
logS-5.4ALOGPS
pKa (strongest acidic)4.29ChemAxon
pKa (strongest basic)1.32ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count6ChemAxon
hydrogen donor count2ChemAxon
polar surface area111.16ChemAxon
rotatable bond count13ChemAxon
refractivity138.16ChemAxon
polarizability57.2ChemAxon
number of rings4ChemAxon
bioavailability0ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD01070
BindingDB50084625
ChEBI3353
ChEMBLCHEMBL35084
Therapeutic Targets DatabaseDAP001145
PharmGKBPA164764517
ATC CodesNot Available
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

1. Neprilysin

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Neprilysin P08473 Details

References:

  1. O’Connell JE, Jardine AG, Davidson G, Connell JM: Candoxatril, an orally active neutral endopeptidase inhibitor, raises plasma atrial natriuretic factor and is natriuretic in essential hypertension. J Hypertens. 1992 Mar;10(3):271-7. Pubmed
  2. Elsner D, Muntze A, Kromer EP, Riegger GA: Effectiveness of endopeptidase inhibition (candoxatril) in congestive heart failure. Am J Cardiol. 1992 Aug 15;70(4):494-8. Pubmed
  3. Plamboeck A, Holst JJ, Carr RD, Deacon CF: Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. Diabetologia. 2005 Sep;48(9):1882-90. Epub 2005 Jul 16. Pubmed
  4. Sansoe G, Aragno M, Mastrocola R, Cutrin JC, Silvano S, Mengozzi G, Smedile A, Rosina F, Danni O, Rizzetto M: Overexpression of kidney neutral endopeptidase (EC 3.4.24.11) and renal function in experimental cirrhosis. Am J Physiol Renal Physiol. 2006 Jun;290(6):F1337-43. Epub 2006 Jan 31. Pubmed
  5. Hirata Y, Suzuki E, Hayakawa H, Matsuoka H, Sugimoto T, Kangawa K, Matsuo H: Mechanisms of the natriuretic effects of neutral endopeptidase inhibition in Dahl salt-sensitive and salt-resistant rats. J Cardiovasc Pharmacol. 1994 Feb;23(2):283-90. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Angiotensin-converting enzyme

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Angiotensin-converting enzyme P12821 Details

References:

  1. Dumoulin MJ, Adam A, Rouleau JL, Lamontagne D: Comparison of a vasopeptidase inhibitor with neutral endopeptidase and angiotensin-converting enzyme inhibitors on bradykinin metabolism in the rat coronary bed. J Cardiovasc Pharmacol. 2001 Apr;37(4):359-66. Pubmed
  2. Kostova E, Jovanoska E, Zafirov D, Jakovski K, Maleska V, Slaninka-Miceska M: Dual inhibition of angiotensin converting enzyme and neutral endopeptidase produces effective blood pressure control in spontaneously hypertensive rats. Bratisl Lek Listy. 2005;106(12):407-11. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on January 20, 2014 11:24