Trandolapril

Identification

Summary

Trandolapril is a prodrug of an ACE inhibitor used to treat hypertension, congestive heart failure, and to improve survival following a myocardial infarction.

Brand Names
Mavik, Tarka
Generic Name
Trandolapril
DrugBank Accession Number
DB00519
Background

Trandolapril is a non-sulhydryl prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is metabolized to its biologically active diacid form, trandolaprilat, in the liver. Trandolaprilat inhibits ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Trandolapril may be used to treat mild to moderate hypertension, to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction, as an adjunct treatment for congestive heart failure, and to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 430.5372
Monoisotopic: 430.246772208
Chemical Formula
C24H34N2O5
Synonyms
  • Trandolapril
  • Trandolaprilum
External IDs
  • RU 44570
  • RU-44570

Pharmacology

Indication

For the treatment of mild to moderate hypertension, as an adjunct in the treatment of congestive heart failure (CHF), to improve survival following myocardial infarction (MI) in individuals who are hemodynamically stable and demonstrate symptoms of left ventricular systolic dysfunction or signs of CHF within a few days following acute MI, and to slow progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Symptomatic treatment ofHeart failure••••••••••••••••••
Used in combination to manageHigh blood pressure (hypertension)••••••••••••••••••
Management ofHigh blood pressure (hypertension)••••••••••••••••••
Used in combination to manageHypertensionCombination Product in combination with: Verapamil (DB00661)••••••••••••••••••• •••••••• •••••••
Symptomatic treatment ofLeft ventricular dysfunction••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Trandolapril is the ethyl ester prodrug of a nonsulfhydryl ACE inhibitor, trandolaprilat. Trandolapril is deesterified in the liver to the diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE than its parent compound. ACE is a peptidyl dipeptidase that is part of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure via a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may further sustain the effects of trandolaprilat by causing increased vasodilation and decreased blood pressure. The blood pressure lowering effect of trandolaprilat is due to a decrease in peripheral vascular resistance, which is not accompanied by significant changes in urinary excretion of chloride or potassium or water or sodium retention.

Mechanism of action

There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Trandolaprilat, the active metabolite of trandolapril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Trandolaprilat also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.

TargetActionsOrganism
AAngiotensin-converting enzyme
inhibitor
Humans
Absorption

~ 40-60% absorbed; extensive first pass metabolism results in a low bioavailability of 4-14%

Volume of distribution
  • 18 L
Protein binding

Serum protein binding of trandolapril is ~ 80% (independent of concentration and not saturable) while that of trandolaprilat is 65 to 94% (concentration-dependent and saturable).

Metabolism

Cleavage of the ester group of trandolapril, primarily in the liver, is responsible for conversion to trandolaprilat, the active metabolite. Seven other metabolites, including diketopiperazine and glucuronide conjugated derivatives of trandolapril and trandolaprilat, have been identified.

Hover over products below to view reaction partners

Route of elimination

After oral administration of trandolapril, about 33% of parent drug and metabolites are recovered in urine, mostly as trandolaprilat, with about 66% in feces.

Half-life

The elimination half lives of trandolapril and trandolaprilat are about 6 and 10 hours, respectively, but, similar to all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase that involves a small fraction of administered drug. This likely represents drug binding to plasma and tissue ACE. The effective half life of elimination for trandolaprilat is 16-24 hours.

Clearance
  • 52 L/h [After approximately 2 mg IV doses]
Adverse Effects
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Toxicity

Most likely clinical manifestations of overdose are symptoms of severe hypotension. Most common adverse effects include cough, headache and dizziness. The oral LD50 of trandolapril in mice was 4875 mg/kg in males and 3990 mg/kg in females. In rats, an oral dose of 5000 mg/kg caused low mortality (1 male out of 5; 0 females). In dogs, an oral dose of 1000 mg/kg did not cause mortality and abnormal clinical signs were not observed.

Pathways
PathwayCategory
Trandolapril Action PathwayDrug action
Trandolapril Metabolism PathwayDrug metabolism
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.
DrugInteraction
AbaloparatideThe risk or severity of adverse effects can be increased when Trandolapril is combined with Abaloparatide.
AcebutololTrandolapril may increase the hypotensive activities of Acebutolol.
AceclofenacThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Aceclofenac is combined with Trandolapril.
AcemetacinThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Acemetacin is combined with Trandolapril.
Acetylsalicylic acidThe therapeutic efficacy of Trandolapril can be decreased when used in combination with Acetylsalicylic acid.
Food Interactions
  • Avoid hypertensive herbs (e.g. bayberry, blue cohosh, cayenne, ephedra, and licorice).
  • Avoid potassium-containing products. Potassium products increase the risk of hyperkalemia.
  • Limit salt intake. Salt may attenuate the antihypertensive effect.
  • Take with or without food. The absorption is unaffected by food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Trandolapril hydrochloride3EY8XK2J4T87725-72-2QNSWMJYOGMUVGO-REWXTUPXSA-N
Active Moieties
NameKindUNIICASInChI Key
TrandolaprilatprodrugRR6866VL0O87679-71-8AHYHTSYNOHNUSH-HXFGRODQSA-N
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MavikCapsule0.5 mgOralBgp Pharma Ulc1998-01-28Not applicableCanada flag
MavikTablet1 mg/1OralAbbvie1996-04-262017-06-30US flag
MavikCapsule2 mgOralBgp Pharma Ulc1998-01-14Not applicableCanada flag
MavikCapsule4 mgOralBgp Pharma Ulc2003-11-01Not applicableCanada flag
MavikTablet4 mg/1OralPhysicians Total Care, Inc.2004-06-25Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Apo-trandolaprilCapsule4 mgOralApotex CorporationNot applicableNot applicableCanada flag
Apo-trandolaprilCapsule0.5 mgOralApotex CorporationNot applicableNot applicableCanada flag
Apo-trandolaprilCapsule2 mgOralApotex CorporationNot applicableNot applicableCanada flag
Apo-trandolaprilCapsule1 mgOralApotex CorporationNot applicableNot applicableCanada flag
Auro-trandolaprilCapsule2 mgOralAuro Pharma Inc2018-09-27Not applicableCanada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
TarkaTrandolapril (1 mg/1) + Verapamil hydrochloride (240 mg/1)Tablet, film coated, extended releaseOralAbbvie1996-10-222018-02-28US flag
TarkaTrandolapril (2 mg) + Verapamil hydrochloride (180 mg)Tablet, extended releaseOralAbbott2002-07-152010-11-12Canada flag
TarkaTrandolapril (2 mg/1) + Verapamil hydrochloride (240 mg/1)Tablet, film coated, extended releaseOralAbbvie1996-10-222021-09-13US flag
TarkaTrandolapril (2 mg/1) + Verapamil hydrochloride (240 mg/1)Tablet, film coated, extended releaseOralPhysicians Total Care, Inc.2005-05-27Not applicableUS flag
TarkaTrandolapril (2 mg/1) + Verapamil hydrochloride (180 mg/1)Tablet, film coated, extended releaseOralAbbvie1996-10-222021-08-14US flag

Categories

ATC Codes
C09AA10 — TrandolaprilC09BB10 — Trandolapril and verapamil
Drug Categories
Chemical TaxonomyProvided by Classyfire
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 / N-acyl-L-alpha-amino acids / Alpha amino acid amides / Indoles and derivatives / Pyrrolidine carboxylic acids / N-acylpyrrolidines / Aralkylamines / Fatty acid esters / Benzene and substituted derivatives / Dicarboxylic acids and derivatives
show 10 more
Substituents
Alpha-amino acid amide / Alpha-amino acid ester / Alpha-amino acid or derivatives / Alpha-dipeptide / Amine / Amino acid / Amino acid or derivatives / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
1T0N3G9CRC
CAS number
87679-37-6
InChI Key
VXFJYXUZANRPDJ-WTNASJBWSA-N
InChI
InChI=1S/C24H34N2O5/c1-3-31-24(30)19(14-13-17-9-5-4-6-10-17)25-16(2)22(27)26-20-12-8-7-11-18(20)15-21(26)23(28)29/h4-6,9-10,16,18-21,25H,3,7-8,11-15H2,1-2H3,(H,28,29)/t16-,18+,19-,20-,21-/m0/s1
IUPAC Name
(2S,3aR,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-octahydro-1H-indole-2-carboxylic acid
SMILES
[H][C@@]12C[C@H](N(C(=O)[C@H](C)N[C@@H](CCC3=CC=CC=C3)C(=O)OCC)[C@@]1([H])CCCC2)C(O)=O

References

Synthesis Reference

Narendra Joshi, Shekhar Bhirud, Buddhavarapu Ramam, Arjun Bodkhe, "Process for the preparation of intermediates of trandolapril and use thereof for the preparation of trandolapril." U.S. Patent US20060079698, issued April 13, 2006.

US20060079698
General References
  1. Berl T: Review: renal protection by inhibition of the renin-angiotensin-aldosterone system. J Renin Angiotensin Aldosterone Syst. 2009 Mar;10(1):1-8. doi: 10.1177/1470320309102747. [Article]
  2. Conen H, Brunner HR: Pharmacologic profile of trandolapril, a new angiotensin-converting enzyme inhibitor. Am Heart J. 1993 May;125(5 Pt 2):1525-31. [Article]
  3. Diaz A, Ducharme A: Update on the use of trandolapril in the management of cardiovascular disorders. Vasc Health Risk Manag. 2008;4(6):1147-58. [Article]
  4. Guay DR: Trandolapril: a newer angiotensin-converting enzyme inhibitor. Clin Ther. 2003 Mar;25(3):713-75. [Article]
  5. Jouquey S, Stepniewski JP, Hamon G: Trandolapril dose-response in spontaneously hypertensive rats: effects on ACE activity, blood pressure, and cardiac hypertrophy. J Cardiovasc Pharmacol. 1994;23 Suppl 4:S16-8. [Article]
  6. Reynolds NA, Wagstaff AJ, Keam SJ: Trandolapril/verapamil sustained release: a review of its use in the treatment of essential hypertension. Drugs. 2005;65(13):1893-914. [Article]
  7. Rubio-Guerra AF, Vargas-Robles H, Vargas-Ayala G, Rodriguez-Lopez L, Escalante-Acosta BA: The effect of trandolapril and its fixed-dose combination with verapamil on circulating adhesion molecules levels in hypertensive patients with type 2 diabetes. Clin Exp Hypertens. 2008 Oct;30(7):682-8. doi: 10.1080/10641960802251941. [Article]
  8. Sanbe A, Tanonaka K, Kobayasi R, Takeo S: Effects of long-term therapy with ACE inhibitors, captopril, enalapril and trandolapril, on myocardial energy metabolism in rats with heart failure following myocardial infarction. J Mol Cell Cardiol. 1995 Oct;27(10):2209-22. [Article]
  9. Torp-Pedersen C, Kober L: Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular function after acute myocardial infarction. TRACE Study Group. Trandolapril Cardiac Evaluation. Lancet. 1999 Jul 3;354(9172):9-12. [Article]
  10. Authors unspecified: Trandolapril: an ACE inhibitor for treatment of hypertension. Med Lett Drugs Ther. 1996 Nov 22;38(988):104-5. [Article]
  11. Wiseman LR, McTavish D: Trandolapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in essential hypertension. Drugs. 1994 Jul;48(1):71-90. [Article]
  12. Zannad F: Trandolapril. How does it differ from other angiotensin converting enzyme inhibitors? Drugs. 1993;46 Suppl 2:172-81; discussion 182. [Article]
  13. FDA Approved Drug Products: Mavik (trandolapril) tablets for oral use [Link]
  14. FDA Approved Drugs: Tarka® extended-release tablets [Link]
Human Metabolome Database
HMDB0014660
KEGG Drug
D00383
PubChem Compound
5484727
PubChem Substance
46508300
ChemSpider
4588590
BindingDB
50369775
RxNav
38454
ChEBI
9649
ChEMBL
CHEMBL1519
ZINC
ZINC000001853205
Therapeutic Targets Database
DAP000583
PharmGKB
PA451737
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Trandolapril
MSDS
Download (57.2 KB)

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableCompletedNot AvailableCoronavirus Disease 2019 (COVID‑19) / COVID / Hypertension1somestatusstop reasonjust information to hide
4CompletedTreatmentCoronary Artery Disease (CAD) / Hypertension1somestatusstop reasonjust information to hide
4CompletedTreatmentDiabetes / Hypertension1somestatusstop reasonjust information to hide
4CompletedTreatmentDiabetes / Hypertension / Proteinuria1somestatusstop reasonjust information to hide
4CompletedTreatmentHeart Failure / Left Ventricular Dysfunction1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
  • Abbott laboratories pharmaceutical products div
  • Aurobindo pharma ltd
  • Cipla ltd
  • Corepharma llc
  • Dr reddys laboratories ltd
  • Epic pharma llc
  • Invagen pharmaceuticals inc
  • Lupin ltd
  • Mylan pharmaceuticals inc
  • Teva pharmaceuticals usa
  • Watson laboratories inc
Packagers
  • Abbott Laboratories Ltd.
  • Arrow Pharm Malta Ltd.
  • Aurobindo Pharma Ltd.
  • BASF Corp.
  • Cipla Ltd.
  • Cobalt Pharmaceuticals Inc.
  • Corepharma LLC
  • DAVA Pharmaceuticals
  • Doctor Reddys Laboratories Ltd.
  • Glenmark Generics Ltd.
  • Greenstone LLC
  • InvaGen Pharmaceuticals Inc.
  • Lupin Pharmaceuticals Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Physicians Total Care Inc.
  • Resource Optimization and Innovation LLC
  • Sandoz
  • Teva Pharmaceutical Industries Ltd.
  • West-Ward Pharmaceuticals
Dosage Forms
FormRouteStrength
CapsuleOral
CapsuleOral0.5 mg
CapsuleOral1 mg
CapsuleOral2 mg
CapsuleOral4 mg
Tablet, extended releaseOral
Tablet, film coated, extended releaseOral
Tablet, film coatedOral
Tablet, delayed releaseOral
Capsule, coatedOral
TabletOral1 mg/1
TabletOral2 mg/1
TabletOral4 mg/1
CapsuleOral
Prices
Unit descriptionCostUnit
Tarka 1-240 mg Controlled Release Tabs3.46USD tab
Tarka 4-240 mg Controlled Release Tabs3.4USD tab
Tarka 1-240 mg tablet sa3.33USD tablet
Tarka 2-180 mg tablet sa3.33USD tablet
Tarka 2-240 mg Controlled Release Tabs3.33USD tab
Tarka 2-240 mg tablet sa3.33USD tablet
Tarka 4-240 mg tablet sa3.33USD tablet
Tarka 2-180 mg Controlled Release Tabs3.29USD tab
Mavik 2 mg tablet1.61USD tablet
Mavik 4 mg tablet1.61USD tablet
Mavik 1 mg tablet1.47USD tablet
Trandolapril 1 mg tablet1.24USD tablet
Trandolapril 2 mg tablet1.23USD tablet
Trandolapril 4 mg tablet1.23USD tablet
Mavik 4 mg Capsule1.03USD capsule
Mavik 2 mg Capsule0.83USD capsule
Mavik 1 mg Capsule0.72USD capsule
Mavik 0.5 mg Capsule0.42USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5744496No1998-04-282015-04-28US flag
CA2023089No2003-01-142010-08-10Canada flag
CA1341206No2001-03-202018-03-20Canada flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)119-123 °CNot Available
logP3.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0207 mg/mLALOGPS
logP1.31ALOGPS
logP1.95Chemaxon
logS-4.3ALOGPS
pKa (Strongest Acidic)3.8Chemaxon
pKa (Strongest Basic)5.21Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area95.94 Å2Chemaxon
Rotatable Bond Count10Chemaxon
Refractivity115.79 m3·mol-1Chemaxon
Polarizability46.96 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9303
Blood Brain Barrier-0.8908
Caco-2 permeable-0.8501
P-glycoprotein substrateSubstrate0.7744
P-glycoprotein inhibitor IInhibitor0.5527
P-glycoprotein inhibitor IIInhibitor0.7759
Renal organic cation transporterNon-inhibitor0.8336
CYP450 2C9 substrateNon-substrate0.8227
CYP450 2D6 substrateNon-substrate0.8935
CYP450 3A4 substrateSubstrate0.5515
CYP450 1A2 substrateNon-inhibitor0.915
CYP450 2C9 inhibitorNon-inhibitor0.785
CYP450 2D6 inhibitorNon-inhibitor0.9018
CYP450 2C19 inhibitorNon-inhibitor0.796
CYP450 3A4 inhibitorNon-inhibitor0.5339
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6906
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.9188
BiodegradationNot ready biodegradable0.9587
Rat acute toxicity2.2048 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9811
hERG inhibition (predictor II)Non-inhibitor0.5531
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-001l-9134000000-c52f8386e44b6f3e4183
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0525900000-d9c0915ea98e09dcb1f2
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-1124900000-5eee64e8c1e5f75edd90
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-08gi-1943200000-de24c6ad53cb95ac9a7d
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-00kf-6904200000-405b8d0e54d6867217cc
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-06vl-4922000000-aba8aed6f26b832aed82
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-2910000000-f746a379c603b8b0333c
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-216.9686721
predicted
DarkChem Lite v0.1.0
[M-H]-223.2352721
predicted
DarkChem Lite v0.1.0
[M-H]-202.76476
predicted
DeepCCS 1.0 (2019)
[M+H]+217.2796721
predicted
DarkChem Lite v0.1.0
[M+H]+223.8521721
predicted
DarkChem Lite v0.1.0
[M+H]+205.16034
predicted
DeepCCS 1.0 (2019)
[M+Na]+216.6994721
predicted
DarkChem Lite v0.1.0
[M+Na]+223.4460721
predicted
DarkChem Lite v0.1.0
[M+Na]+211.07362
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity (PubMed:15615692, PubMed:20826823, PubMed:2558109, PubMed:4322742, PubMed:7523412, PubMed:7683654). Composed of two similar catalytic domains, each possessing a functional active site, with different selectivity for substrates (PubMed:10913258, PubMed:1320019, PubMed:1851160, PubMed:19773553, PubMed:7683654, PubMed:7876104). Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin (PubMed:11432860, PubMed:1851160, PubMed:19773553, PubMed:23056909, PubMed:4322742). Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response (PubMed:15615692, PubMed:2558109, PubMed:4322742, PubMed:6055465, PubMed:6270633, PubMed:7683654). Acts as a regulator of synaptic transmission by mediating cleavage of neuropeptide hormones, such as substance P, neurotensin or enkephalins (PubMed:15615692, PubMed:6208535, PubMed:6270633, PubMed:656131). Catalyzes degradation of different enkephalin neuropeptides (Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Phe and possibly Met-enkephalin-Arg-Gly-Leu) (PubMed:2982830, PubMed:6270633, PubMed:656131). Acts as a regulator of synaptic plasticity in the nucleus accumbens of the brain by mediating cleavage of Met-enkephalin-Arg-Phe, a strong ligand of Mu-type opioid receptor OPRM1, into Met-enkephalin (By similarity). Met-enkephalin-Arg-Phe cleavage by ACE decreases activation of OPRM1, leading to long-term synaptic potentiation of glutamate release (By similarity). Also acts as a regulator of hematopoietic stem cell differentiation by mediating degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) (PubMed:26403559, PubMed:7876104, PubMed:8257427, PubMed:8609242). Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin, an antagonist peptide of the cannabinoid receptor CNR1 (PubMed:18077343). Involved in amyloid-beta metabolism by catalyzing degradation of Amyloid-beta protein 40 and Amyloid-beta protein 42 peptides, thereby preventing plaque formation (PubMed:11604391, PubMed:16154999, PubMed:19773553). Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones (PubMed:10336644, PubMed:2983326, PubMed:7683654, PubMed:9371719). Degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) and amyloid-beta proteins is mediated by the N-terminal catalytic domain, while angiotensin I and cholecystokinin cleavage is mediated by the C-terminal catalytic region (PubMed:10336644, PubMed:19773553, PubMed:7876104)
Specific Function
actin binding
Gene Name
ACE
Uniprot ID
P12821
Uniprot Name
Angiotensin-converting enzyme
Molecular Weight
149713.675 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  2. Piepho RW: Overview of the angiotensin-converting-enzyme inhibitors. Am J Health Syst Pharm. 2000 Oct 1;57 Suppl 1:S3-7. [Article]
  3. Song JC, White CM: Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet. 2002;41(3):207-24. [Article]
  4. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs (PubMed:18762277, PubMed:7980644, PubMed:9169443, PubMed:9490062). Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl-CoA ester (PubMed:18762277, PubMed:7980644, PubMed:9169443, PubMed:9490062). Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine (PubMed:7980644). Catalyzes the transesterification of cocaine to form cocaethylene (PubMed:7980644). Displays fatty acid ethyl ester synthase activity, catalyzing the ethyl esterification of oleic acid to ethyloleate (PubMed:7980644). Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes of 2-arachidonoylglycerol and prostaglandins (PubMed:21049984). Hydrolyzes cellular cholesteryl esters to free cholesterols and promotes reverse cholesterol transport (RCT) by facilitating both the initial and final steps in the process (PubMed:11015575, PubMed:16024911, PubMed:16971496, PubMed:18762277). First of all, allows free cholesterol efflux from macrophages to extracellular cholesterol acceptors and secondly, releases free cholesterol from lipoprotein-delivered cholesteryl esters in the liver for bile acid synthesis or direct secretion into the bile (PubMed:16971496, PubMed:18599737, PubMed:18762277)
Specific Function
carboxylesterase activity
Gene Name
CES1
Uniprot ID
P23141
Uniprot Name
Liver carboxylesterase 1
Molecular Weight
62520.62 Da
References
  1. Zhu HJ, Appel DI, Johnson JA, Chavin KD, Markowitz JS: Role of carboxylesterase 1 and impact of natural genetic variants on the hydrolysis of trandolapril. Biochem Pharmacol. 2009 Apr 1;77(7):1266-72. doi: 10.1016/j.bcp.2008.12.017. Epub 2009 Jan 6. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Electrogenic proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides. Transports neutral and monovalently charged peptides with a proton to peptide stoichiometry of 1:1 or 2:1 (By similarity) (PubMed:15521010, PubMed:18367661, PubMed:19685173, PubMed:26320580, PubMed:7896779, PubMed:8914574, PubMed:9835627). Primarily responsible for the absorption of dietary di- and tripeptides from the small intestinal lumen (By similarity). Mediates transepithelial transport of muramyl and N-formylated bacterial dipeptides contributing to recognition of pathogenic bacteria by the mucosal immune system (PubMed:15521010, PubMed:9835627)
Specific Function
dipeptide transmembrane transporter activity
Gene Name
SLC15A1
Uniprot ID
P46059
Uniprot Name
Solute carrier family 15 member 1
Molecular Weight
78805.265 Da
References
  1. Knutter I, Wollesky C, Kottra G, Hahn MG, Fischer W, Zebisch K, Neubert RH, Daniel H, Brandsch M: Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41. doi: 10.1124/jpet.108.143339. Epub 2008 Aug 19. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides (PubMed:16434549, PubMed:18367661, PubMed:7756356). Transports neutral and anionic dipeptides with a proton to peptide stoichiometry of 2:1 or 3:1 (By similarity). In kidney, involved in the absorption of circulating di- and tripeptides from the glomerular filtrate (PubMed:7756356). Can also transport beta-lactam antibiotics, such as the aminocephalosporin cefadroxil, and other antiviral and anticancer drugs (PubMed:16434549). Transports the dipeptide-like aminopeptidase inhibitor bestatin (By similarity). Also able to transport carnosine (PubMed:31073693). Involved in innate immunity by promoting the detection of microbial pathogens by NOD-like receptors (NLRs) (By similarity). Mediates transport of bacterial peptidoglycans across the plasma membrane or, in macrophages, the phagosome membrane: catalyzes the transport of certain bacterial peptidoglycans, such as muramyl dipeptide (MDP), the NOD2 ligand (PubMed:20406817)
Specific Function
dipeptide transmembrane transporter activity
Gene Name
SLC15A2
Uniprot ID
Q16348
Uniprot Name
Solute carrier family 15 member 2
Molecular Weight
81782.77 Da
References
  1. Knutter I, Wollesky C, Kottra G, Hahn MG, Fischer W, Zebisch K, Neubert RH, Daniel H, Brandsch M: Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41. doi: 10.1124/jpet.108.143339. Epub 2008 Aug 19. [Article]

Drug created at June 13, 2005 13:24 / Updated at November 03, 2024 19:35