Cilazapril

Identification

Summary

Cilazapril is an ACE inhibitor used for the management of hypertension and heart failure.

Brand Names
Inhibace
Generic Name
Cilazapril
DrugBank Accession Number
DB01340
Background

Cilazapril is an ACE inhibtor class drug used in the treatment of hypertension and heart failure. It belongs to the angiotensin-converting enzyme inhibitors (ACE inhibitors) class of drugs. It is a prodrug that is hydrolyzed after absorption to its main metabolite cilazaprilat. It is branded as Inhibace in Canada and other countries, Vascace and Dynorm in a number of European countries, among many other names. None of these varieties are available in the United States.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 417.4986
Monoisotopic: 417.226371117
Chemical Formula
C22H31N3O5
Synonyms
  • Cilazapril
  • Cilazapril anhydrous
  • Cilazaprilum
External IDs
  • Ro 31-2848

Pharmacology

Indication

Cilazapril is an ACE inhibtor class drug used in the treatment of hypertension and heart failure.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Adjunct therapy in treatment ofCongestive heart failure••••••••••••
Used in combination to manageHypertensionCombination Product in combination with: Hydrochlorothiazide (DB00999)••••••••••••
Management ofMild essential hypertension••••••••••••
Management ofModerate essential hypertension••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Cilazapril inhibits the production angiotensin II. By doing so, it decreases sodium and water reabsorption (via aldosterone) and it decreases vasoconstriction. The combined effect of this is a decrease in vascular resistance, and therefore, blood pressure. The absolute bioavailability of cilazaprilat after oral administration of cilazapril is 57% based on urinary recovery data. (The absolute bioavailability of cilazaprilat after oral administration of cilazaprilat is 19%.) Ingestion of food immediately before the administration of cilazapril reduces the average peak plasma concentration of cilazaprilat by 29%, delays the peak by one hour and reduces the bioavailability of cilazaprilat by 14%. These pharmacokinetic changes have little influence on plasma ACE inhibition.

Mechanism of action

Cilazapril is a pyridazine ACE inhibitor. It competes with angiotensin I for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II. As angiotensin II is a vasoconstrictor and a negative feedback mediator for renin activity, lower angiotensin II levels results in a decrease in blood pressure, an increase in renin activity, and stimulation of baroreceptor reflex mechanisms. Kininase II, an enzyme which degrades the vasodilator bradykinin, is identical to ACE and may also be inhibited.

TargetActionsOrganism
AAngiotensin-converting enzyme
inhibitor
Humans
Absorption

Maximum plasma concentrations of cilazaprilat are reached within two hours after administration of cilazapril.

Volume of distribution

Not Available

Protein binding

Maximum ACE inhibition is greater than 90% after 1 to 5 mg cilazapril. Maximum ACE inhibition is 70 to 80% after 0.5 mg cilazapril. Dose proportionality is observed following the administration of 1 to 5 mg cilazapril. Apparent non-proportionality is observed at 0.5 mg reflective of the binding to ACE. The higher doses of cilazapril are associated with longer duration of maximum ACE inhibition.

Metabolism

Hover over products below to view reaction partners

Route of elimination

Cilazaprilat is eliminated unchanged by the kidneys. The total urinary recovery of cilazaprilat after intravenous administration of 2.5 mg is 91%.

Half-life

Half-lives for the periods 1 to 4 hours and 1 to 7 days after the intravenous administration of 2.5 mg cilazaprilat are 0.90 and 46.2 hours respectively.

Clearance

Total clearance is 12.3 L/h and renal clearance is 10.8 L/h. The total urinary recovery of cilazaprilat following the oral administration of 2.5 mg cilazapril is 52.6%.

Adverse Effects
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Toxicity

Limited data are available with regard to overdosage in humans. The most likely manifestations are hypotension, which may be severe, hyperkalaemia, hyponatraemia and renal impairment with metabolic acidosis. Treatment should be mainly symptomatic and supportive.

Pathways
PathwayCategory
Cilazapril Action PathwayDrug action
Cilazapril 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 Cilazapril is combined with Abaloparatide.
AcebutololAcebutolol may increase the hypotensive activities of Cilazapril.
AceclofenacThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Aceclofenac is combined with Cilazapril.
AcemetacinThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Acemetacin is combined with Cilazapril.
Acetylsalicylic acidThe therapeutic efficacy of Cilazapril can be decreased when used in combination with Acetylsalicylic acid.
Food Interactions
  • Take with or without food. Food decreases absorption, but not to a clinically significant extent.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Cilazapril monohydrate19KW7PI29F92077-78-6JQRZBPFGBRIWSN-YOTVLOEGSA-N
International/Other Brands
Dynorm (Roche) / Inhibestril (Teva) / Vascace (Roche) / Zapril (Mylan) / Zobox (Hemofarm)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CilazaprilTablet5.0 mgOralCobalt LaboratoriesNot applicableNot applicableCanada flag
CilazaprilTablet2.5 mgOralSanis Health Inc2010-05-312017-07-31Canada flag
CilazaprilTablet5 mgOralSanis Health Inc2010-05-312014-08-01Canada flag
CilazaprilTablet2.5 mgOralCobalt LaboratoriesNot applicableNot applicableCanada flag
CilazaprilTablet1 mgOralSanis Health Inc2010-05-312017-07-31Canada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Apo-cilazaprilTablet1 mgOralApotex Corporation2007-02-01Not applicableCanada flag
Apo-cilazaprilTablet5 mgOralApotex Corporation2007-02-01Not applicableCanada flag
Apo-cilazaprilTablet2.5 mgOralApotex Corporation2007-02-01Not applicableCanada flag
Dom-cilazaprilTablet1.0 mgOralDominion PharmacalNot applicableNot applicableCanada flag
Dom-cilazaprilTablet5.0 mgOralDominion PharmacalNot applicableNot applicableCanada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ACEPRIX PLUS 5 MG/12.5 MG FILM TABLET, 30 ADETCilazapril (5 mg) + Hydrochlorothiazide (12.5 mg)Tablet, film coatedOralALİ RAİF İLAÇ SAN. A.Ş.2010-06-28Not applicableTurkey flag
Apo-cilazapril/hctzCilazapril monohydrate (5 mg) + Hydrochlorothiazide (12.5 mg)TabletOralApotex Corporation2006-08-23Not applicableCanada flag
DYNORM PLUSCilazapril monohydrate (5 mg/1) + Hydrochlorothiazide (12.5 mg/1)Tablet, film coatedOral2010-09-01Not applicableGermany flag
Inhibace PlusCilazapril monohydrate (5 mg) + Hydrochlorothiazide (12.5 mg)TabletOralCheplapharm Arzneimittel Gmbh Germany1999-04-01Not applicableCanada flag
INHIBACE PLUS 5 MG TABLET, 28 ADETCilazapril monohydrate (5 mg) + Hydrochlorothiazide (12.5 mg)TabletOralDeva Holding A.S.2008-12-312024-01-23Turkey flag

Categories

ATC Codes
C09BA08 — Cilazapril and diureticsC09AA08 — Cilazapril
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 / 1,2-diazepanes / Fatty acid esters / Aralkylamines / Pyridazines and derivatives / Dicarboxylic acids and derivatives / Diazinanes / Benzene and substituted derivatives / Amino acids / Carboxylic acid hydrazides
show 8 more
Substituents
1,2-diazepane / 1,2-diazinane / Alpha-amino acid ester / Alpha-amino acid or derivatives / Alpha-dipeptide / Amine / Amino acid / Amino acid or derivatives / Aralkylamine / Aromatic heteropolycyclic compound
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
8Q9454114Q
CAS number
88768-40-5
InChI Key
HHHKFGXWKKUNCY-FHWLQOOXSA-N
InChI
InChI=1S/C22H31N3O5/c1-2-30-22(29)18(13-12-16-8-4-3-5-9-16)23-17-10-6-14-24-15-7-11-19(21(27)28)25(24)20(17)26/h3-5,8-9,17-19,23H,2,6-7,10-15H2,1H3,(H,27,28)/t17-,18-,19-/m0/s1
IUPAC Name
(1S,9S)-9-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}-10-oxo-octahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid
SMILES
CCOC(=O)[C@H](CCC1=CC=CC=C1)N[C@H]1CCCN2CCC[C@H](N2C1=O)C(O)=O

References

Synthesis Reference

Attwood, M. R.; Hassall, C. H.; Kr�Hn, A.; Lawton, G.; Redshaw, S. (1986). "The design and synthesis of the Angiotensin Converting Enzyme inhibitor Cilazapril and related bicyclic compounds". Journal of the Chemical Society, Perkin Transactions 1: 1011. doi:10.1039/P19860001011

US20060293517
General References
  1. Fasanella d'Amore T, Bussien JP, Nussberger J, Waeber B, Turini GA, Brunner HR, Kler L, Francis RJ: Effects of single doses of the converting enzyme inhibitor cilazapril in normal volunteers. J Cardiovasc Pharmacol. 1987 Jan;9(1):26-31. [Article]
Human Metabolome Database
HMDB0015433
KEGG Drug
D07699
PubChem Compound
56330
PubChem Substance
46505231
ChemSpider
50831
RxNav
21102
ChEBI
3698
ChEMBL
CHEMBL515606
ZINC
ZINC000003781951
Therapeutic Targets Database
DAP000912
PharmGKB
PA164748302
Drugs.com
Drugs.com Drug Page
Wikipedia
Cilazapril
FDA label
Download (114 KB)
MSDS
Download (81.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentCardiovascular Disease (CVD) / Type 2 Diabetes Mellitus1
Not AvailableUnknown StatusTreatmentGlomerulonephritis , IGA1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral2.5 mg
TabletOral5 mg
TabletOral
Tablet, film coatedOral2.5 mg/1
Tablet, film coatedOral5 mg/1
Tablet, film coatedOral
Tablet, film coatedOral
TabletOral1 mg
Tablet, film coatedOral1 MG
Tablet, film coatedOral5 MG
Tablet, coatedOral
TabletOral1.0 mg
TabletOral2.5 mg
TabletOral5.0 mg
Prices
Unit descriptionCostUnit
Inhibace 5 mg Tablet0.94USD tablet
Inhibace 2.5 mg Tablet0.81USD tablet
Inhibace 1 mg Tablet0.7USD tablet
Apo-Cilazapril 5 mg Tablet0.52USD tablet
Co Cilazapril 5 mg Tablet0.52USD tablet
Mylan-Cilazapril 5 mg Tablet0.52USD tablet
Novo-Cilazapril 5 mg Tablet0.52USD tablet
Pms-Cilazapril 5 mg Tablet0.52USD tablet
Apo-Cilazapril 2.5 mg Tablet0.45USD tablet
Co Cilazapril 2.5 mg Tablet0.45USD tablet
Mylan-Cilazapril 2.5 mg Tablet0.45USD tablet
Novo-Cilazapril 2.5 mg Tablet0.45USD tablet
Pms-Cilazapril 2.5 mg Tablet0.45USD tablet
Apo-Cilazapril 1 mg Tablet0.39USD tablet
Mylan-Cilazapril 1 mg Tablet0.39USD tablet
Novo-Cilazapril 1 mg Tablet0.39USD tablet
Pms-Cilazapril 1 mg Tablet0.39USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US20060293517No2004-03-082024-03-08US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)98 ºC with decomposition Not Available
water solubilityWater (25 ºC) 0.5 g/100 mL Not Available
logP0.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility1.06 mg/mLALOGPS
logP-0.2ALOGPS
logP0.22Chemaxon
logS-2.6ALOGPS
pKa (Strongest Acidic)3.4Chemaxon
pKa (Strongest Basic)5.06Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area99.18 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity110.56 m3·mol-1Chemaxon
Polarizability44.73 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9157
Blood Brain Barrier-0.9402
Caco-2 permeable-0.7698
P-glycoprotein substrateSubstrate0.8727
P-glycoprotein inhibitor IInhibitor0.7775
P-glycoprotein inhibitor IINon-inhibitor0.8788
Renal organic cation transporterNon-inhibitor0.8318
CYP450 2C9 substrateNon-substrate0.7876
CYP450 2D6 substrateNon-substrate0.8283
CYP450 3A4 substrateSubstrate0.5396
CYP450 1A2 substrateNon-inhibitor0.882
CYP450 2C9 inhibitorNon-inhibitor0.7804
CYP450 2D6 inhibitorNon-inhibitor0.7503
CYP450 2C19 inhibitorNon-inhibitor0.816
CYP450 3A4 inhibitorNon-inhibitor0.8201
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8376
Ames testNon AMES toxic0.6023
CarcinogenicityNon-carcinogens0.9028
BiodegradationNot ready biodegradable0.9942
Rat acute toxicity2.3700 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9311
hERG inhibition (predictor II)Inhibitor0.6303
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-MSsplash10-0006-3119000000-cf816839d9e62aaeb51d
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-0004900000-e1b1a9a581d9c7f14901
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-0033900000-a34151d1918703508609
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00r6-0129500000-3bf9140cde17a01eda47
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-00tf-4197300000-bb4ac129d11cf4199ef4
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-004l-7933000000-173860d0d21ab8b8c0ed
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-003l-2393000000-68c3a1d96174954bedda
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]-205.5676215
predicted
DarkChem Lite v0.1.0
[M-H]-206.4854215
predicted
DarkChem Lite v0.1.0
[M-H]-197.26562
predicted
DeepCCS 1.0 (2019)
[M+H]+205.8920215
predicted
DarkChem Lite v0.1.0
[M+H]+207.7480215
predicted
DarkChem Lite v0.1.0
[M+H]+199.6612
predicted
DeepCCS 1.0 (2019)
[M+Na]+205.7132215
predicted
DarkChem Lite v0.1.0
[M+Na]+207.6128215
predicted
DarkChem Lite v0.1.0
[M+Na]+205.67699
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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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
References
  1. Yoshiyama M, Takeuchi K, Omura T, Kim S, Yamagishi H, Toda I, Teragaki M, Akioka K, Iwao H, Yoshikawa J: Effects of candesartan and cilazapril on rats with myocardial infarction assessed by echocardiography. Hypertension. 1999 Apr;33(4):961-8. [Article]
  2. Kihara M, Mitsui MK, Mitsui Y, Okuda K, Nakasaka Y, Takahashi M, Schmelzer JD: Altered vasoreactivity to angiotensin II in experimental diabetic neuropathy: role of nitric oxide. Muscle Nerve. 1999 Jul;22(7):920-5. [Article]
  3. Mervaala E, Dehmel B, Gross V, Lippoldt A, Bohlender J, Milia AF, Ganten D, Luft FC: Angiotensin-converting enzyme inhibition and AT1 receptor blockade modify the pressure-natriuresis relationship by additive mechanisms in rats with human renin and angiotensinogen genes. J Am Soc Nephrol. 1999 Aug;10(8):1669-80. [Article]
  4. Rosendorff C, Patton J, Radford HM, Kalliatakis B: Alpha-adrenergic and angiotensin II pressor sensitivity in hypertensive patients treated with an angiotensin-converting enzyme inhibitor. J Cardiovasc Pharmacol. 1992;19 Suppl 6:S105-9. [Article]
  5. Hannedouche T, Ikeni A, Marques LP, Natov S, Dechaux M, Schmitt F, Lacour B, Grunfeld JP: Renal effects of angiotensin II in normotensive subjects on short-term cilazapril treatment. J Cardiovasc Pharmacol. 1992;19 Suppl 6:S25-7. [Article]
  6. Tylicki L, Rutkowski P, Renke M, Larczynski W, Aleksandrowicz E, Lysiak-Szydlowska W, Rutkowski B: Triple pharmacological blockade of the renin-angiotensin-aldosterone system in nondiabetic CKD: an open-label crossover randomized controlled trial. Am J Kidney Dis. 2008 Sep;52(3):486-93. doi: 10.1053/j.ajkd.2008.02.297. Epub 2008 Apr 18. [Article]
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Takara K, Kakumoto M, Tanigawara Y, Funakoshi J, Sakaeda T, Okumura K: Interaction of digoxin with antihypertensive drugs via MDR1. Life Sci. 2002 Feb 15;70(13):1491-500. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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. 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
Peptide:proton symporter activity
Specific Function
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides.
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 30, 2007 18:09 / Updated at March 18, 2024 16:48