DrugBank: Candoxatril (DB00616)

targets (2)

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

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

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
PubChem Compound	5362417
PubChem Substance	46509011
ChemSpider	4515031
BindingDB	50084625
ChEBI	3353
ChEMBL	3353
Therapeutic Targets Database	DAP001145
Drug Product Database	0

ATC Codes

Not Available

AHFS Codes

Not Available

PDB Entries

1DMT

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 Gene: MME Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 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 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 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 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 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 Gene: ACE Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 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

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

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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
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
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
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
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
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

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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
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.