Identification

Name
Candoxatril
Accession Number
DB00616  (APRD00027)
Type
Small Molecule
Groups
Experimental
Description

Candoxatril is the orally-active prodrug of candoxatrilat (UK-73967), a potent neutral endopeptidase (NEP) inhibitor.

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 IDs
UK-79,300 / UK-79300
Active Moieties
NameKindUNIICASInChI Key
Candoxatrilatprodrug7WU8BZ90TH123122-54-3ACZWIDANLCXHBM-HRCADAONSA-N
Categories
UNII
ACP75508EE
CAS number
123122-55-4
Weight
Average: 515.6383
Monoisotopic: 515.288302671
Chemical Formula
C29H41NO7
InChI Key
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[C@H](CC1(CCCC1)C(=O)N[C@H]1CC[C@H](CC1)C(O)=O)C(=O)OC1=CC2=C(CCC2)C=C1

Pharmacology

Indication
Not Available
Pharmacodynamics
Not Available
Mechanism of action

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.

TargetActionsOrganism
ANeprilysin
inhibitor
Human
UAngiotensin-converting enzyme
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololCandoxatril may increase the hypotensive activities of Acebutolol.
AceclofenacThe therapeutic efficacy of Candoxatril can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Candoxatril can be decreased when used in combination with Acemetacin.
Acetylsalicylic acidThe therapeutic efficacy of Candoxatril can be decreased when used in combination with Acetylsalicylic acid.
AlclofenacThe therapeutic efficacy of Candoxatril can be decreased when used in combination with Alclofenac.
AlfuzosinAlfuzosin may increase the hypotensive activities of Candoxatril.
AliskirenCandoxatril may increase the hypotensive activities of Aliskiren.
AlminoprofenThe therapeutic efficacy of Candoxatril can be decreased when used in combination with Alminoprofen.
AlprenololCandoxatril may increase the hypotensive activities of Alprenolol.
AmbrisentanCandoxatril may increase the hypotensive activities of Ambrisentan.
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0014754
KEGG Drug
D01070
PubChem Compound
5362417
PubChem Substance
46509011
ChemSpider
16736409
BindingDB
50084625
ChEBI
3353
ChEMBL
CHEMBL35084
Therapeutic Targets Database
DAP001145
PharmGKB
PA164764517
Wikipedia
Candoxatril

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Indanes
Sub Class
Not Available
Direct Parent
Indanes
Alternative Parents
Fatty acid esters / Fatty amides / Dicarboxylic acids and derivatives / Secondary carboxylic acid amides / Carboxylic acid esters / Dialkyl ethers / Carboxylic acids / Organopnictogen compounds / Organonitrogen compounds / Organic oxides
show 2 more
Substituents
Indane / Fatty acid ester / Dicarboxylic acid or derivatives / Fatty amide / Fatty acyl / Carboxamide group / Secondary carboxylic acid amide / Carboxylic acid ester / Ether / Dialkyl ether
show 11 more
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
dicarboxylic acid monoester, monocarboxylic acid, monocarboxylic acid amide (CHEBI:3353)

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 peptide...
Gene Name
MME
Uniprot ID
P08473
Uniprot Name
Neprilysin
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...
Gene Name
ACE
Uniprot ID
P12821
Uniprot Name
Angiotensin-converting enzyme
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]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:47