Enalaprilat
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
Structure for Enalaprilat (DB09477)
- Synonyms
- Enalaprilat anhydrous
- Product Ingredients
Ingredient UNII CAS InChI Key Enalaprilat dihydrate GV0O7ES0R3 84680-54-6 MZYVOFLIPYDBGD-MLZQUWKJSA-N - Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Enalaprilat Injection, solution 1.25 mg/1mL Intravenous Mayne Pharma (USA) Inc. 2007-03-16 Not applicable US 
Enalaprilat Injection USP Solution 1.25 mg Intravenous Sterimax Inc 2012-09-10 Not applicable Canada 
Vasotec IV Solution 1.25 mg Intravenous Sandoz Canada Incorporated 1992-12-31 Not applicable Canada - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Enalaprilat Injection 2.5 mg/2mL Intravenous Hikma Farmaceutica 2008-12-23 2008-12-23 US Enalaprilat Injection 1.25 mg/1mL Intravenous West Ward Pharmaceutical 2008-12-23 Not applicable US Enalaprilat Injection, solution 1.25 mg/1mL Intravenous Teva Parenteral Medicines, Inc. 2005-10-06 Not applicable US Enalaprilat Injection 1.25 mg/1mL Intravenous Bedford Pharmaceuticals 2000-08-23 2012-07-31 US Enalaprilat Injection 1.25 mg/1mL Intravenous Hikma Farmaceutica 2008-12-23 2008-12-23 US Enalaprilat Injection, solution 1.25 mg/1mL Intravenous Hospira, Inc. 2005-08-24 Not applicable US Enalaprilat Injection 1.25 mg/1mL Intravenous Bedford Pharmaceuticals 2000-08-23 2012-07-31 US Enalaprilat Injection 2.5 mg/2mL Intravenous West Ward Pharmaceutical 2008-12-23 Not applicable US Enalaprilat Injection, solution 1.25 mg/1mL Intravenous Teva Parenteral Medicines, Inc. 2005-10-06 Not applicable US Enalaprilat Injection 1.25 mg/1mL Intravenous Cardinal Health 2000-08-23 2012-07-31 US - Categories
- Agents Acting on the Renin-Angiotensin System
- Agents causing angioedema
- Agents causing hyperkalemia
- Amino Acids, Peptides, and Proteins
- Angiotensin-Converting Enzyme Inhibitors
- Antihypertensive Agents
- Cardiovascular Agents
- Decreased Blood Pressure
- Dipeptides
- Enalapril
- Enzyme Inhibitors
- Hypotensive Agents
- Oligopeptides
- Peptides
- Protease Inhibitors
- 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
Target Actions Organism AAngiotensin-converting enzyme inhibitorHuman UB1 bradykinin receptor Not Available Human - 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
Drug Interaction (4R)-limonene The risk or severity of adverse effects can be increased when (4R)-limonene is combined with Enalaprilat. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Enalaprilat. Abacavir The serum concentration of Abacavir can be decreased when it is combined with Enalaprilat. Acebutolol Acebutolol may increase the hypotensive activities of Enalaprilat. Aceclofenac The risk or severity of adverse effects can be increased when Aceclofenac is combined with Enalaprilat. Acemetacin The therapeutic efficacy of Enalaprilat can be decreased when used in combination with Acemetacin. Acetaminophen Acetaminophen may decrease the excretion rate of Enalaprilat which could result in a higher serum level. Acetylsalicylic acid The risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Acetylsalicylic acid is combined with Enalaprilat. Acyclovir Acyclovir may decrease the excretion rate of Enalaprilat which could result in a higher serum level. Adefovir Dipivoxil Adefovir Dipivoxil may decrease the excretion rate of Enalaprilat which could result in a higher serum level. - Food Interactions
- Not Available
References
- General References
- 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]
- 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
Phase Status Purpose Conditions Count 3 Completed Treatment Congestive Cardiomyopathy / High Blood Pressure (Hypertension) 1 4 Completed Basic Science Type 2 Diabetes Mellitus 1 Not Available Completed Not Available Salt-sensitive Hypertension 1 Not Available Completed Health Services Research Idiopathic orthostatic hypotension / Spinal Cord Injuries (SCI) 1 Not Available Completed Treatment CVA (Cerebrovascular Accident) / Intracerebral Hemorrhage / Intracranial Hemorrhages 1 Not Available Completed Treatment High Blood Pressure (Hypertension) / Type 2 Diabetes Mellitus 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Injection Intravenous 1.25 mg/1mL Injection Intravenous 2.5 mg/2mL Injection, solution Intravenous 1.25 mg/1mL Solution Intravenous 1.25 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.876 mg/mL ALOGPS logP -0.09 ALOGPS logP -1.1 ChemAxon logS -2.6 ALOGPS pKa (Strongest Acidic) 3.13 ChemAxon pKa (Strongest Basic) 7.83 ChemAxon Physiological Charge -1 ChemAxon Hydrogen Acceptor Count 6 ChemAxon Hydrogen Donor Count 3 ChemAxon Polar Surface Area 106.94 Å2 ChemAxon Rotatable Bond Count 8 ChemAxon Refractivity 90.06 m3·mol-1 ChemAxon Polarizability 35.82 Å3 ChemAxon Number of Rings 2 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available LC-MS/MS Spectrum - LC-ESI-qTof , Positive LC-MS/MS Not 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
- 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