Identification

Name
Temocapril
Accession Number
DB08836
Type
Small Molecule
Groups
Experimental, 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 IDs
CS-622
Product Ingredients
IngredientUNIICASInChI Key
Temocapril hydrochloride8G820I95VP110221-44-8XDDQNOKKZKHBIX-ASBZXGSUSA-N
International/Other Brands
Acecol (Sankyo)
Categories
UNII
18IZ008EU6
CAS number
111902-57-9
Weight
Average: 476.609
Monoisotopic: 476.143963396
Chemical Formula
C23H28N2O5S2
InChI Key
FIQOFIRCTOWDOW-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)[C@H](CCC1=CC=CC=C1)N[C@H]1CS[C@@H](CN(CC(O)=O)C1=O)C1=CC=CS1

Pharmacology

Indication

Temocapril 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).

Pharmacodynamics

Temocapril 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 action
TargetActionsOrganism
UAngiotensin-converting enzyme
inhibitor
Human
Absorption

Temocapril is rapidly absorbed in the gastrointestinal tract and converted into the diacid (active) metabolite, which inhibits ACE in plasma.

Volume of distribution
Not Available
Protein binding

99.5%, including those with renal impairment.

Metabolism
Not Available
Route of elimination

Temocapril is eliminated primarily through the liver and kidneys.

Half life

13.1 hours in patients with normal liver function.

Clearance

19.4% urinary recovery.

Toxicity

In rats, whether or male or female, the LD50 values of temocapril were higher than 5000 mg/kg.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Temocapril Action PathwayDrug action
Temocapril Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(4R)-limoneneThe risk or severity of adverse effects can be increased when (4R)-limonene is combined with Temocapril.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Temocapril.
AbacavirThe serum concentration of Abacavir can be decreased when it is combined with Temocapril.
AcebutololAcebutolol may increase the hypotensive activities of Temocapril.
AceclofenacThe risk or severity of adverse effects can be increased when Aceclofenac is combined with Temocapril.
AcemetacinThe therapeutic efficacy of Temocapril can be decreased when used in combination with Acemetacin.
Acetylsalicylic acidThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Acetylsalicylic acid is combined with Temocapril.
AlclofenacThe risk or severity of adverse effects can be increased when Alclofenac is combined with Temocapril.
AlfuzosinAlfuzosin may increase the hypotensive activities of Temocapril.
AliskirenAliskiren may increase the hypotensive, nephrotoxic, and hyperkalemic activities of Temocapril.
Food Interactions
Not Available

References

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
Human Metabolome Database
HMDB0061720
KEGG Drug
D08566
PubChem Compound
443874
PubChem Substance
175427114
ChemSpider
391964
ChEBI
135771
ChEMBL
CHEMBL2110627
Drugs.com
Drugs.com Drug Page
Wikipedia
Temocapril
ATC Codes
C09AA14 — Temocapril
MSDS
Download (569 KB)

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
melting point (°C)decomposes 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 RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

Spectra

Mass Spec (NIST)
Download (163 KB)
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 dipeptides. These are organic compounds containing a sequence of exactly two alpha-amino acids joined by a peptide bond.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Dipeptides
Alternative Parents
Alpha amino acid esters / Aralkylamines / Fatty acid esters / Dicarboxylic acids and derivatives / Benzene and substituted derivatives / Thiophenes / Tertiary carboxylic acid amides / Heteroaromatic compounds / Amino acids / Lactams
show 9 more
Substituents
Alpha-dipeptide / Alpha-amino acid ester / Alpha-amino acid or derivatives / Fatty acid ester / Aralkylamine / Monocyclic benzene moiety / Dicarboxylic acid or derivatives / Fatty acyl / Benzenoid / Tertiary carboxylic acid amide
show 24 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not 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...
Gene Name
ACE
Uniprot ID
P12821
Uniprot Name
Angiotensin-converting enzyme
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
Uniprot Name
Solute carrier family 15 member 1
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 inhibit...
Gene Name
SLCO1A2
Uniprot ID
P46721
Uniprot Name
Solute carrier organic anion transporter family member 1A2
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]

Drug created on February 19, 2013 17:04 / Updated on October 01, 2018 16:22