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Identification
NameCandoxatril
Accession NumberDB00616  (APRD00027)
TypeSmall Molecule
GroupsApproved
Description

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

Structure
Thumb
Synonyms
[4(S)-cis]-4-[[[1-[3-[(2,3-dihydro-1H-Indeb5-yl)oxy]-2-[(2-methoxyethoxy)methyl]-3-oxopropyl]cyclopentyl]carbonyl]amino]cyclohexanecarboxylic acid
4-({1-[(S)-2-(indan-5-yloxycarbonyl)-3-(2-methoxy-ethoxy)-propyl]-cyclopentanecarbonyl}-amino)-cyclohexanecarboxylic acid
External Identifiers
  • UK-79,300
  • UK-79300
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIACP75508EE
CAS number123122-55-4
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]cyclopentaneamido}cyclohexane-1-carboxylic acid
SMILES
COCCOC[[email protected]](CC1(CCCC1)C(=O)N[[email protected]]1CC[[email protected]](CC1)C(O)=O)C(=O)OC1=CC2=C(CCC2)C=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as indanes. These are compounds containing an indane moiety, which consists of a cyclopentane fused to a benzene ring.
KingdomOrganic compounds
Super ClassBenzenoids
ClassIndanes
Sub ClassNot Available
Direct ParentIndanes
Alternative Parents
Substituents
  • Indane
  • Fatty acid ester
  • Cyclohexylamine
  • Fatty acyl
  • Fatty amide
  • Dicarboxylic acid or derivatives
  • Secondary carboxylic acid amide
  • Carboxylic acid ester
  • Carboxamide group
  • Ether
  • Dialkyl ether
  • Carboxylic acid
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External Descriptors
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.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
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
PropertyValueProbability
Human Intestinal Absorption+0.9142
Blood Brain Barrier+0.8437
Caco-2 permeable-0.6787
P-glycoprotein substrateSubstrate0.8158
P-glycoprotein inhibitor INon-inhibitor0.8213
P-glycoprotein inhibitor IINon-inhibitor0.9075
Renal organic cation transporterNon-inhibitor0.7707
CYP450 2C9 substrateNon-substrate0.7497
CYP450 2D6 substrateNon-substrate0.7492
CYP450 3A4 substrateSubstrate0.6952
CYP450 1A2 substrateNon-inhibitor0.7035
CYP450 2C9 inhibitorNon-inhibitor0.7548
CYP450 2D6 inhibitorNon-inhibitor0.8484
CYP450 2C19 inhibitorNon-inhibitor0.6641
CYP450 3A4 inhibitorNon-inhibitor0.9144
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8421
Ames testNon AMES toxic0.62
CarcinogenicityNon-carcinogens0.9494
BiodegradationNot ready biodegradable0.8614
Rat acute toxicity2.5001 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9833
hERG inhibition (predictor II)Non-inhibitor0.5652
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP3.7Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00225 mg/mLALOGPS
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 Area111.16 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity138.16 m3·mol-1ChemAxon
Polarizability57.2 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:15283675, PubMed:8168535). Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond (PubMed:17101991). Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9 (PubMed:15283675). Involved in the degradation of at...
Gene Name:
MME
Uniprot ID:
P08473
Molecular Weight:
85513.225 Da
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:1315825 ]
  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:1386491 ]
  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:16025254 ]
  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:16449355 ]
  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:7511759 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety.
Gene Name:
ACE
Uniprot ID:
P12821
Molecular Weight:
149713.675 Da
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:11300648 ]
  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:16642666 ]
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Drug created on June 13, 2005 07:24 / Updated on May 02, 2016 13:47