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Identification
NameTemocapril
Accession NumberDB08836
TypeSmall Molecule
GroupsExperimental, Investigational
Description

Temocapril is a prodrug-type angiotensin-I converting enzyme (ACE) inhibitor not approved for use in the United States, but is approved in Japan and South Korea. Temocapril can also be used in hemodialysis patients without risk of serious accumulation.

Structure
Thumb
Synonyms
Temocaprilum
External Identifiers
  • CS-622
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AcecolSankyo
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Temocapril hydrochloride
110221-44-8
Thumb
  • InChI Key: XDDQNOKKZKHBIX-ASBZXGSUSA-N
  • Monoisotopic Mass: 512.120641135
  • Average Mass: 513.07
DBSALT000171
Categories
UNII18IZ008EU6
CAS number111902-57-9
WeightAverage: 476.609
Monoisotopic: 476.143963396
Chemical FormulaC23H28N2O5S2
InChI KeyFIQOFIRCTOWDOW-BJLQDIEVSA-N
InChI
InChI=1S/C23H28N2O5S2/c1-2-30-23(29)17(11-10-16-7-4-3-5-8-16)24-18-15-32-20(19-9-6-12-31-19)13-25(22(18)28)14-21(26)27/h3-9,12,17-18,20,24H,2,10-11,13-15H2,1H3,(H,26,27)/t17-,18-,20-/m0/s1
IUPAC Name
2-[(2S,6R)-6-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}-5-oxo-2-(thiophen-2-yl)-1,4-thiazepan-4-yl]acetic acid
SMILES
CCOC(=O)[[email protected]](CCC1=CC=CC=C1)N[[email protected]]1CS[C@@H](CN(CC(O)=O)C1=O)C1=CC=CS1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as alpha amino acid esters. These are ester derivatives of alpha amino acids.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentAlpha amino acid esters
Alternative Parents
Substituents
  • Alpha-amino acid ester
  • Phenylpropylamine
  • Aralkylamine
  • Fatty acid ester
  • Fatty acyl
  • Benzenoid
  • Dicarboxylic acid or derivatives
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Thiophene
  • Tertiary carboxylic acid amide
  • Tertiary amine
  • Lactam
  • Carboxylic acid ester
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Dialkylthioether
  • Thioether
  • Secondary amine
  • Secondary aliphatic amine
  • Carboxylic acid
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationTemocapril is an ACE inhibitor primarily indicated in the treatment of hypertension and congestive heart failure, diabetic nephropathy, and improvement of prognosis for coronary artery diseases (including acute myocardial infarction).
PharmacodynamicsTemocapril is a prodrug of its active metabolite (and diacid form) temocaprilat which contains a thiazepine ring. Temocaprilat has slightly higher potency than enalaprilat in ACE inhibition isolated from rabbit lung. ACE inhibitors exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility.). When compared with other Angiotensin-converting Enzyme Inhibitors, temocapril's advantages include a rapid onset of action and what research suggests is tighter vascular ACE binding than enalaprilat.
Mechanism of actionNot Available
Related Articles
AbsorptionTemocapril is rapidly absorbed in the gastrointestinal tract and converted into the diacid (active) metabolite, which inhibits ACE in plasma.
Volume of distributionNot Available
Protein binding99.5%, including those with renal impairment.
MetabolismNot Available
Route of eliminationTemocapril is eliminated primarily through the liver and kidneys.
Half life13.1 hours in patients with normal liver function.
Clearance

19.4% urinary recovery.

ToxicityIn rats, whether or male or female, the LD50 values of temocapril were higher than 5000 mg/kg.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Temocapril Action PathwayDrug actionSMP00733
Temocapril Metabolism PathwayDrug metabolismSMP00732
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9707
Blood Brain Barrier-0.8501
Caco-2 permeable-0.6871
P-glycoprotein substrateSubstrate0.8016
P-glycoprotein inhibitor INon-inhibitor0.6373
P-glycoprotein inhibitor IINon-inhibitor0.9056
Renal organic cation transporterNon-inhibitor0.8744
CYP450 2C9 substrateNon-substrate0.6676
CYP450 2D6 substrateNon-substrate0.8686
CYP450 3A4 substrateSubstrate0.5082
CYP450 1A2 substrateNon-inhibitor0.7748
CYP450 2C9 inhibitorNon-inhibitor0.6996
CYP450 2D6 inhibitorNon-inhibitor0.8016
CYP450 2C19 inhibitorInhibitor0.5371
CYP450 3A4 inhibitorNon-inhibitor0.746
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7297
Ames testNon AMES toxic0.7962
CarcinogenicityNon-carcinogens0.8965
BiodegradationNot ready biodegradable0.9584
Rat acute toxicity2.3397 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9862
hERG inhibition (predictor II)Inhibitor0.5523
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
melting pointdecomposes at 187Not Available
water solubility<1 mg/mLNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00342 mg/mLALOGPS
logP2.46ALOGPS
logP2.04ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)3.88ChemAxon
pKa (Strongest Basic)5.14ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area95.94 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity124.1 m3·mol-1ChemAxon
Polarizability49.28 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (163 KB)
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Tsuji A: Transporter-mediated Drug Interactions. Drug Metab Pharmacokinet. 2002;17(4):253-74. [PubMed:15618677 ]
  2. Furuta S, Kiyosawa K, Higuchi M, Kasahara H, Saito H, Shioya H, Oguchi H: Pharmacokinetics of temocapril, an ACE inhibitor with preferential biliary excretion, in patients with impaired liver function. Eur J Clin Pharmacol. 1993;44(4):383-5. [PubMed:8513851 ]
  3. Nakashima M, Yamamoto J, Shibata M, Uematsu T, Shinjo H, Akahori T, Shioya H, Sugiyama K, Kawahara Y: Pharmacokinetics of temocapril hydrochloride, a novel angiotensin converting enzyme inhibitor, in renal insufficiency. Eur J Clin Pharmacol. 1992;43(6):657-9. [PubMed:1493850 ]
  4. Yasunari K, Maeda K, Nakamura M, Watanabe T, Yoshikawa J, Asada A: Pharmacological and clinical studies with temocapril, an angiotensin converting enzyme inhibitor that is excreted in the bile. Cardiovasc Drug Rev. 2004 Fall;22(3):189-98. [PubMed:15492767 ]
  5. Clearance of Temocapril and Enalapril during Haemodialysis Treatment [Link]
External Links
ATC CodesC09AA14
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (569 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

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. Furuta S, Kiyosawa K, Higuchi M, Kasahara H, Saito H, Shioya H, Oguchi H: Pharmacokinetics of temocapril, an ACE inhibitor with preferential biliary excretion, in patients with impaired liver function. Eur J Clin Pharmacol. 1993;44(4):383-5. [PubMed:8513851 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Proton-dependent oligopeptide secondary active transmembrane transporter activity
Specific Function:
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products.
Gene Name:
SLC15A1
Uniprot ID:
P46059
Molecular Weight:
78805.265 Da
References
  1. Tsuji A: Transporter-mediated Drug Interactions. Drug Metab Pharmacokinet. 2002;17(4):253-74. [PubMed:15618677 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity). Selectively inhibited by the grapefruit juice component naringin.
Gene Name:
SLCO1A2
Uniprot ID:
P46721
Molecular Weight:
74144.105 Da
References
  1. Ishizuka H, Konno K, Naganuma H, Nishimura K, Kouzuki H, Suzuki H, Stieger B, Meier PJ, Sugiyama Y: Transport of temocaprilat into rat hepatocytes: role of organic anion transporting polypeptide. J Pharmacol Exp Ther. 1998 Oct;287(1):37-42. [PubMed:9765319 ]
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Drug created on February 19, 2013 17:04 / Updated on May 07, 2016 20:51