Identification

Name
Enalaprilat
Accession Number
DB09477
Type
Small Molecule
Groups
Approved
Description

Enalaprilat is the active metabolite of the orally available pro-drug, enalapril. Used in the treatment of hypertension, enalapril is an ACE inhibitor that prevents Angiotensin Converting Enzyme (ACE) from transforming angiotensin I into angiotensin II. As angiotensin II is responsible for vasoconstriction and sodium reabsorption in the proximal tubule of the kidney, down-regulation of this protein results in reduced blood pressure and blood fluid volume. Enalaprilat was originally created to overcome the limitations of the first ACE inhibitor, captopril, which had numerous side effects and left a metallic taste in the mouth. Removal of the problematic thiol group from captopril resulted in enalaprilat, which was then modified further with an ester to create the orally available pro-drug enalapril.

Enalaprilat is poorly orally available and is therefore only available as an intravenous injection for the treatment of hypertension when oral therapy is not possible.

Structure
Thumb
Synonyms
  • Enalaprilat anhydrous
Product Ingredients
IngredientUNIICASInChI Key
Enalaprilat dihydrateGV0O7ES0R384680-54-6MZYVOFLIPYDBGD-MLZQUWKJSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EnalaprilatInjection, solution1.25 mg/1mLIntravenousMayne Pharma (USA) Inc.2007-03-16Not applicableUs
Enalaprilat Injection USPSolution1.25 mgIntravenousSterimax Inc2012-09-10Not applicableCanada
Vasotec IVSolution1.25 mgIntravenousSandoz Canada Incorporated1992-12-31Not applicableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EnalaprilatInjection2.5 mg/2mLIntravenousHikma Farmaceutica2008-12-232008-12-23Us
EnalaprilatInjection1.25 mg/1mLIntravenousWest Ward Pharmaceutical2008-12-23Not applicableUs
EnalaprilatInjection, solution1.25 mg/1mLIntravenousTeva Parenteral Medicines, Inc.2005-10-06Not applicableUs
EnalaprilatInjection1.25 mg/1mLIntravenousBedford Pharmaceuticals2000-08-232012-07-31Us
EnalaprilatInjection1.25 mg/1mLIntravenousHikma Farmaceutica2008-12-232008-12-23Us
EnalaprilatInjection, solution1.25 mg/1mLIntravenousHospira, Inc.2005-08-24Not applicableUs
EnalaprilatInjection1.25 mg/1mLIntravenousBedford Pharmaceuticals2000-08-232012-07-31Us
EnalaprilatInjection2.5 mg/2mLIntravenousWest Ward Pharmaceutical2008-12-23Not applicableUs
EnalaprilatInjection, solution1.25 mg/1mLIntravenousTeva Parenteral Medicines, Inc.2005-10-06Not applicableUs
EnalaprilatInjection1.25 mg/1mLIntravenousCardinal Health2000-08-232012-07-31Us
Categories
UNII
Q508Q118JM
CAS number
76420-72-9
Weight
Average: 348.3936
Monoisotopic: 348.168521888
Chemical Formula
C18H24N2O5
InChI Key
LZFZMUMEGBBDTC-QEJZJMRPSA-N
InChI
InChI=1S/C18H24N2O5/c1-12(16(21)20-11-5-8-15(20)18(24)25)19-14(17(22)23)10-9-13-6-3-2-4-7-13/h2-4,6-7,12,14-15,19H,5,8-11H2,1H3,(H,22,23)(H,24,25)/t12-,14-,15-/m0/s1
IUPAC Name
(2S)-1-[(2S)-2-{[(1S)-1-carboxy-3-phenylpropyl]amino}propanoyl]pyrrolidine-2-carboxylic acid
SMILES
[H][C@@](C)(N[C@@]([H])(CCC1=CC=CC=C1)C(O)=O)C(=O)N1CCC[C@@]1([H])C(O)=O

Pharmacology

Indication

Enalaprilat injection is indicated for the treatment of hypertension when oral therapy is not practical.

Associated Conditions
Pharmacodynamics

Enalaprilat injection results in the reduction of both supine and standing systolic and diastolic blood pressure, usually with no orthostatic component. Symptomatic postural hypotension is therefore infrequent, although it might be anticipated in volume-depleted patients. The onset of action usually occurs within fifteen minutes of administration with the maximum effect occurring within one to four hours. The abrupt withdrawal of enalaprilat has not been associated with a rapid increase in blood pressure. The duration of hemodynamic effects appears to be dose-related. However, for the recommended dose, the duration of action in most patients is approximately six hours. Following administration of enalapril, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension.

Mechanism of action

Enalaprilat is the active metabolite of the orally available pro-drug, enalapril. Used in the treatment of hypertension, enalapril is an ACE inhibitor that prevents Angiotensin Converting Enzyme (ACE) from transforming angiotensin I into angiotensin II. As angiotensin II is responsible for vasoconstriction and sodium reabsorption in the proximal tubule of the kidney, down-regulation of this protein results in reduced blood pressure and blood fluid volume

TargetActionsOrganism
AAngiotensin-converting enzyme
inhibitor
Human
UB1 bradykinin receptorNot AvailableHuman
Absorption

Enalaprilat is poorly absorbed following oral administration, and is therefore only available as an intravenous injection.

Volume of distribution
Not Available
Protein binding

Enalaprilat is approximately 50% bound to plasma proteins. (Davies, et al. 1984)

Metabolism

Both enalapril and enalaprilat undergo renal excretion without further metabolism.

Route of elimination

Excretion of enalaprilat is primarily renal with more than 90 percent of an administered dose recovered in the urine as unchanged drug within 24 hours.

Half life

11 hr

Clearance

The disposition of enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. Renal clearance was 158 ± 47 ml/min.

Toxicity

Adverse experiences occurring in 0.5 to 1.0 percent of patients in controlled clinical trials included: myocardial infarction, fatigue, dizziness, fever, rash and constipation. Angioedema has also been reported in patients receiving enalaprilat, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalaprilat should be discontinued and appropriate therapy instituted immediately .

Rarer adverse effects that are less likely, but should be monitored for, include development of anaphylaxis, hypotension, agranulocytosis, hepatic failure, hyperkalemia, and persistent cough.

Furthermore, ACE inhibitors should be avoided during pregnancy as they can cause fetal and neonatal morbidity and death. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. Use during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Affected organisms
Not Available
Pathways
Not Available
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 Enalaprilat.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Enalaprilat.
AbacavirThe serum concentration of Abacavir can be decreased when it is combined with Enalaprilat.
AcebutololAcebutolol may increase the hypotensive activities of Enalaprilat.
AceclofenacThe risk or severity of adverse effects can be increased when Aceclofenac is combined with Enalaprilat.
AcemetacinThe therapeutic efficacy of Enalaprilat can be decreased when used in combination with Acemetacin.
AcetaminophenAcetaminophen may decrease the excretion rate of Enalaprilat which could result in a higher serum level.
Acetylsalicylic acidThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Acetylsalicylic acid is combined with Enalaprilat.
AcyclovirAcyclovir may decrease the excretion rate of Enalaprilat which could result in a higher serum level.
Adefovir DipivoxilAdefovir Dipivoxil may decrease the excretion rate of Enalaprilat which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Ulm EH: Enalapril maleate (MK-421), a potent, nonsulfhydryl angiotensin-converting enzyme inhibitor: absorption, disposition, and metabolism in man. Drug Metab Rev. 1983;14(1):99-110. [PubMed:6301792]
  2. Davies RO, Gomez HJ, Irvin JD, Walker JF: An overview of the clinical pharmacology of enalapril. Br J Clin Pharmacol. 1984;18 Suppl 2:215S-229S. [PubMed:6099737]
External Links
Human Metabolome Database
HMDB0041886
KEGG Drug
D03769
KEGG Compound
C11720
PubChem Compound
5462501
PubChem Substance
347827859
ChemSpider
4575429
BindingDB
50367254
ChEBI
4786
ChEMBL
CHEMBL577
HET
EAL
RxList
RxList Drug Page
Wikipedia
Enalaprilat
AHFS Codes
  • 24:32.04 — Angiotensin-converting Enzyme Inhibitors
PDB Entries
1uze / 2x90
FDA label
Download (2.99 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentCongestive Cardiomyopathy / High Blood Pressure (Hypertension)1
4CompletedBasic ScienceType 2 Diabetes Mellitus1
Not AvailableCompletedNot AvailableSalt-sensitive Hypertension1
Not AvailableCompletedHealth Services ResearchIdiopathic orthostatic hypotension / Spinal Cord Injuries (SCI)1
Not AvailableCompletedTreatmentCVA (Cerebrovascular Accident) / Intracerebral Hemorrhage / Intracranial Hemorrhages1
Not AvailableCompletedTreatmentHigh Blood Pressure (Hypertension) / Type 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous1.25 mg/1mL
InjectionIntravenous2.5 mg/2mL
Injection, solutionIntravenous1.25 mg/1mL
SolutionIntravenous1.25 mg
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.876 mg/mLALOGPS
logP-0.09ALOGPS
logP-1.1ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)3.13ChemAxon
pKa (Strongest Basic)7.83ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area106.94 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity90.06 m3·mol-1ChemAxon
Polarizability35.82 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-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
Proline and derivatives / N-acyl-L-alpha-amino acids / Alpha amino acid amides / L-alpha-amino acids / Pyrrolidine carboxylic acids / N-acylpyrrolidines / Aralkylamines / Dicarboxylic acids and derivatives / Benzene and substituted derivatives / Tertiary carboxylic acid amides
show 8 more
Substituents
Alpha-dipeptide / N-acyl-alpha-amino acid / Proline or derivatives / N-acyl-alpha amino acid or derivatives / N-acyl-l-alpha-amino acid / Alpha-amino acid amide / Alpha-amino acid / Alpha-amino acid or derivatives / L-alpha-amino acid / N-acylpyrrolidine
show 26 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
dipeptide, dicarboxylic acid (CHEBI:4786)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Peptide binding
Specific Function
This is a receptor for bradykinin. Could be a factor in chronic pain and inflammation.
Gene Name
BDKRB1
Uniprot ID
P46663
Uniprot Name
B1 bradykinin receptor
Molecular Weight
40494.29 Da
References
  1. Ignjatovic T, Tan F, Brovkovych V, Skidgel RA, Erdos EG: Novel mode of action of angiotensin I converting enzyme inhibitors: direct activation of bradykinin B1 receptor. J Biol Chem. 2002 May 10;277(19):16847-52. Epub 2002 Mar 5. [PubMed:11880373]

Drug created on November 30, 2015 12:10 / Updated on October 16, 2018 05:48