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targets (2)
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Identification
Name Candoxatril
Accession Number DB00616 (APRD00027)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Brand names
  • Candoxatrilat
Brand name mixtures Not Available
Categories
  • Antihypertensive Agents
  • Protease Inhibitors
  • Prodrugs
CAS number 118785-03-8
Weight Average: 515.6383
Monoisotopic: 515.288302671
Chemical Formula C29H41NO7
InChI Key InChIKey=ZTWZVMIYIIVABD-RZMWZJFBSA-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
Plain Text
IUPAC Name
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)NC1CCC(CC1)C(O)=O)C(=O)OC1=CC2=C(CCC2)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Indanes
  • Phenylacetates
Substructures
  • Carbonyl Compounds
  • Carboxylic Acids and Derivatives
  • Hydroxy Compounds
  • Indanes
  • Acetates
  • Phenols and Derivatives
  • Amino Ketones
  • Phenylacetates
  • Ethers
  • Benzene and Derivatives
  • Aromatic compounds
  • Anisoles
  • Carboxamides and Derivatives
  • Phenyl Esters
Pharmacology
Indication For treatment of hypertension, improve exercise capacity in patients with CHF receiving angiotensin converting enzyme inhibition.
Pharmacodynamics 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 in man.
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.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism
Route of elimination Not Available
Half life Not Available
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms Not Available
Prices Not Available
Patents Not Available
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
logP 3.7 PhysProp
Predicted Properties
Property Value Source
water solubility 2.25e-03 g/l ALOGPS
logP 3.55 ALOGPS
logP 4.68 ChemAxon Molconvert
logS -5.36 ALOGPS
pKa 15.24 ChemAxon Molconvert
hydrogen acceptor count 6 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 111.16 ChemAxon Molconvert
rotatable bond count 13 ChemAxon Molconvert
refractivity 138.16 ChemAxon Molconvert
polarizability 57.81 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D01070 Link_out
PubChem Compound 5362417 Link_out
PubChem Substance 46509011 Link_out
ChemSpider 4515031 Link_out
BindingDB 50084625 Link_out
ChEBI 3353 Link_out
ChEMBL 3353 Link_out
Therapeutic Targets Database DAP001145 Link_out
Drug Product Database 0 Link_out
ATC Codes Not Available
AHFS Codes Not Available
PDB Entries
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Food Interactions Not Available
Targets

1. Neprilysin

Pharmacological action: yes
Actions: inhibitor

Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond. Involved in the degradation of atrial natriuretic factor (ANF)

Organism class: human
UniProt ID: P08473 Link_out
Gene: MME Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: inhibitor

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

Organism class: human
UniProt ID: P12821 Link_out
Gene: ACE Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 April 19, 2011 15:05

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.