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

Similar Structures

Synonyms

Enalaprilat
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
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Enalaprilat	Injection, solution	1.25 mg/1mL	Intravenous	Mayne Pharma (USA) Inc.	2007-03-16	Not applicable
Enalaprilat Injection USP	Solution		Intravenous	Sterimax Inc	2012-09-10	Not applicable
Vasotec IV	Solution		Intravenous	Sandoz Canada Incorporated	1992-12-31	Not applicable

Additional Data Available

Application Number

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Enalaprilat	Injection	1.25 mg/1mL	Intravenous	West-Ward Pharmaceuticals Corp	2008-12-23	Not applicable
Enalaprilat	Injection	1.25 mg/1mL	Intravenous	Bedford Pharmaceuticals	2000-08-23	2012-07-31
Enalaprilat	Injection, solution	1.25 mg/1mL	Intravenous	Teva Parenteral Medicines, Inc.	2005-10-06	Not applicable
Enalaprilat	Injection	1.25 mg/1mL	Intravenous	Bedford Pharmaceuticals	2000-08-23	2012-07-31
Enalaprilat	Injection	2.5 mg/2mL	Intravenous	Hikma Farmaceutica	2008-12-23	2008-12-23
Enalaprilat	Injection, solution	1.25 mg/1mL	Intravenous	Hospira, Inc.	2005-08-24	Not applicable
Enalaprilat	Injection, solution	1.25 mg/1mL	Intravenous	Teva Parenteral Medicines, Inc.	2005-10-06	Not applicable
Enalaprilat	Injection	1.25 mg/1mL	Intravenous	Hikma Farmaceutica	2008-12-23	2008-12-23
Enalaprilat	Injection	2.5 mg/2mL	Intravenous	West-Ward Pharmaceuticals Corp	2008-12-23	Not applicable
Enalaprilat	Injection	1.25 mg/1mL	Intravenous	Cardinal Health	2000-08-23	2012-07-31

Additional Data Available

Application Number

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

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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

Target	Actions	Organism
AAngiotensin-converting enzyme	inhibitor	Humans
UB1 bradykinin receptor	Not Available	Humans

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Additional Data Available

Adverse Effects

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Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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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

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
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1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid	1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid may decrease the antihypertensive activities of Enalaprilat.
1-benzylimidazole	1-benzylimidazole may decrease the antihypertensive activities of Enalaprilat.
2,5-Dimethoxy-4-ethylamphetamine	2,5-Dimethoxy-4-ethylamphetamine may decrease the antihypertensive activities of Enalaprilat.
2,5-Dimethoxy-4-ethylthioamphetamine	2,5-Dimethoxy-4-ethylthioamphetamine may decrease the antihypertensive activities of Enalaprilat.
4-Bromo-2,5-dimethoxyamphetamine	4-Bromo-2,5-dimethoxyamphetamine may decrease the antihypertensive activities of Enalaprilat.
4-Methoxyamphetamine	4-Methoxyamphetamine may decrease the antihypertensive activities of Enalaprilat.
5-methoxy-N,N-dimethyltryptamine	5-methoxy-N,N-dimethyltryptamine may decrease the antihypertensive activities of 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	Abacavir may decrease the excretion rate of Enalaprilat which could result in a higher serum level.
Abediterol	Abediterol may decrease the antihypertensive activities of Enalaprilat.

Additional Data Available

Extended Description

Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

A severity rating for each drug interaction, from minor to major.

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Evidence Level

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Action

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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	Orthostatic Hypotension / Spinal Cord Injuries (SCI)	1
Not Available	Completed	Treatment	Cerebral Hemorrhage / Cerebrovascular Accident / 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

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
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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

Details1. Angiotensin-converting enzyme

Kind: Protein
Organism: Humans
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

Details2. B1 bradykinin receptor

Kind: Protein
Organism: Humans
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 November 16, 2019 10:45

Enalaprilat

Identification

Structure for Enalaprilat (DB09477)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References