Candoxatril
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Identification
- Generic Name
- Candoxatril
- DrugBank Accession Number
- DB00616
- Background
Candoxatril is the orally-active prodrug of candoxatrilat (UK-73967), a potent neutral endopeptidase (NEP) inhibitor.
- Type
- Small Molecule
- Groups
- Experimental
- Structure
- Weight
- Average: 515.6383
Monoisotopic: 515.288302671 - Chemical Formula
- C29H41NO7
- 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
- Candoxatril
- External IDs
- UK-79,300
- UK-79300
Pharmacology
- Indication
Not Available
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- 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.
Target Actions Organism ANeprilysin inhibitorHumans UAngiotensin-converting enzyme inhibitorHumans - 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
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbaloparatide Abaloparatide may increase the hypotensive activities of Candoxatril. Acebutolol Candoxatril may increase the hypotensive activities of Acebutolol. Aceclofenac The therapeutic efficacy of Candoxatril can be decreased when used in combination with Aceclofenac. Acemetacin The therapeutic efficacy of Candoxatril can be decreased when used in combination with Acemetacin. Acetylsalicylic acid Acetylsalicylic acid may decrease the antihypertensive activities of Candoxatril. - Food Interactions
- Not Available
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Active Moieties
Name Kind UNII CAS InChI Key Candoxatrilat prodrug 7WU8BZ90TH 123122-54-3 ACZWIDANLCXHBM-HRCADAONSA-N
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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
- Aromatic homopolycyclic compound / Carbonyl group / Carboxamide group / Carboxylic acid / Carboxylic acid derivative / Carboxylic acid ester / Dialkyl ether / Dicarboxylic acid or derivatives / Ether / Fatty acid ester show 11 more
- Molecular Framework
- Aromatic homopolycyclic compounds
- External Descriptors
- dicarboxylic acid monoester, monocarboxylic acid, monocarboxylic acid amide (CHEBI:3353)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- ACP75508EE
- CAS number
- 123122-55-4
- 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
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
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP 3.7 Not Available - Predicted Properties
Property Value Source Water Solubility 0.00225 mg/mL ALOGPS logP 3.55 ALOGPS logP 4.68 Chemaxon logS -5.4 ALOGPS pKa (Strongest Acidic) 4.29 Chemaxon pKa (Strongest Basic) 0.48 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 111.16 Å2 Chemaxon Rotatable Bond Count 13 Chemaxon Refractivity 138.16 m3·mol-1 Chemaxon Polarizability 57.31 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - 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 inhibitor Non-inhibitor 0.7548 CYP450 2D6 inhibitor Non-inhibitor 0.8484 CYP450 2C19 inhibitor Non-inhibitor 0.6641 CYP450 3A4 inhibitor 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
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 240.8726267 predictedDarkChem Lite v0.1.0 [M-H]- 234.8494529 predictedDarkChem Lite v0.1.0 [M-H]- 243.0039267 predictedDarkChem Lite v0.1.0 [M-H]- 219.588 predictedDeepCCS 1.0 (2019) [M+H]+ 241.6071267 predictedDarkChem Lite v0.1.0 [M+H]+ 218.8083499 predictedDarkChem Lite v0.1.0 [M+H]+ 241.0544267 predictedDarkChem Lite v0.1.0 [M+H]+ 221.98357 predictedDeepCCS 1.0 (2019) [M+Na]+ 241.6005267 predictedDarkChem Lite v0.1.0 [M+Na]+ 225.4130144 predictedDarkChem Lite v0.1.0 [M+Na]+ 241.5345267 predictedDarkChem Lite v0.1.0 [M+Na]+ 227.94556 predictedDeepCCS 1.0 (2019)
Targets
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1. DetailsNeprilysin
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:15283675, PubMed:6208535, PubMed:6349683, 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, PubMed:6349683). Catalyzes cleavage of bradykinin, substance P and neurotensin peptides (PubMed:6208535). Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9 (PubMed:15283675, PubMed:6349683). Involved in the degradation of atrial natriuretic factor (ANF) and brain natriuretic factor (BNP(1-32)) (PubMed:16254193, PubMed:2531377, PubMed:2972276). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers (PubMed:20876573)
- Specific Function
- cardiolipin binding
- Gene Name
- MME
- Uniprot ID
- P08473
- Uniprot Name
- Neprilysin
- Molecular Weight
- 85513.225 Da
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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
2. DetailsAngiotensin-converting enzyme
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity (PubMed:15615692, PubMed:20826823, PubMed:2558109, PubMed:4322742, PubMed:7523412, PubMed:7683654). Composed of two similar catalytic domains, each possessing a functional active site, with different selectivity for substrates (PubMed:10913258, PubMed:1320019, PubMed:1851160, PubMed:19773553, PubMed:7683654, PubMed:7876104). Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin (PubMed:11432860, PubMed:1851160, PubMed:19773553, PubMed:23056909, PubMed:4322742). Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response (PubMed:15615692, PubMed:2558109, PubMed:4322742, PubMed:6055465, PubMed:6270633, PubMed:7683654). Acts as a regulator of synaptic transmission by mediating cleavage of neuropeptide hormones, such as substance P, neurotensin or enkephalins (PubMed:15615692, PubMed:6208535, PubMed:6270633, PubMed:656131). Catalyzes degradation of different enkephalin neuropeptides (Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Phe and possibly Met-enkephalin-Arg-Gly-Leu) (PubMed:2982830, PubMed:6270633, PubMed:656131). Acts as a regulator of synaptic plasticity in the nucleus accumbens of the brain by mediating cleavage of Met-enkephalin-Arg-Phe, a strong ligand of Mu-type opioid receptor OPRM1, into Met-enkephalin (By similarity). Met-enkephalin-Arg-Phe cleavage by ACE decreases activation of OPRM1, leading to long-term synaptic potentiation of glutamate release (By similarity). Also acts as a regulator of hematopoietic stem cell differentiation by mediating degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) (PubMed:26403559, PubMed:7876104, PubMed:8257427, PubMed:8609242). Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin, an antagonist peptide of the cannabinoid receptor CNR1 (PubMed:18077343). Involved in amyloid-beta metabolism by catalyzing degradation of Amyloid-beta protein 40 and Amyloid-beta protein 42 peptides, thereby preventing plaque formation (PubMed:11604391, PubMed:16154999, PubMed:19773553). Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones (PubMed:10336644, PubMed:2983326, PubMed:7683654, PubMed:9371719). Degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) and amyloid-beta proteins is mediated by the N-terminal catalytic domain, while angiotensin I and cholecystokinin cleavage is mediated by the C-terminal catalytic region (PubMed:10336644, PubMed:19773553, PubMed:7876104)
- Specific Function
- actin binding
- Gene Name
- ACE
- Uniprot ID
- P12821
- Uniprot Name
- Angiotensin-converting enzyme
- Molecular Weight
- 149713.675 Da
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. [Article]
- 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. [Article]
Drug created at June 13, 2005 13:24 / Updated at October 21, 2024 12:36