Identification

Name
Cilazapril
Accession Number
DB01340
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
Synonyms
  • Cilazapril
  • Cilazapril anhydrous
  • Cilazaprilum
External IDs
Ro 31-2848
Product Ingredients
IngredientUNIICASInChI Key
Cilazapril monohydrate19KW7PI29F92077-78-6JQRZBPFGBRIWSN-YOTVLOEGSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CilazaprilTablet1 mgOralSanis Health Inc2010-05-31Not applicableCanada
CilazaprilTablet2.5 mgOralCobalt LaboratoriesNot applicableNot applicableCanada
CilazaprilTablet1.0 mgOralCobalt LaboratoriesNot applicableNot applicableCanada
CilazaprilTablet2.5 mgOralSanis Health Inc2010-05-31Not applicableCanada
CilazaprilTablet5 mgOralSanis Health Inc2010-05-312014-08-01Canada
CilazaprilTablet5.0 mgOralCobalt LaboratoriesNot applicableNot applicableCanada
Co CilazaprilTablet2.5 mgOralCobalt Laboratories2007-02-06Not applicableCanada
Co CilazaprilTablet1.0 mgOralCobalt LaboratoriesNot applicableNot applicableCanada
Co CilazaprilTablet5.0 mgOralCobalt Laboratories2007-02-06Not applicableCanada
InhibaceTablet2.5 mgOralHoffmann La Roche1993-12-31Not applicableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-cilazaprilTablet5 mgOralApotex Corporation2007-02-01Not applicableCanada
Apo-cilazaprilTablet2.5 mgOralApotex Corporation2007-02-01Not applicableCanada
Apo-cilazaprilTablet1 mgOralApotex Corporation2007-02-01Not applicableCanada
Dom-cilazaprilTablet5.0 mgOralDominion PharmacalNot applicableNot applicableCanada
Dom-cilazaprilTablet2.5 mgOralDominion PharmacalNot applicableNot applicableCanada
Dom-cilazaprilTablet1.0 mgOralDominion PharmacalNot applicableNot applicableCanada
Mylan-cilazaprilTablet1 mgOralMylan Pharmaceuticals2006-07-21Not applicableCanada
Mylan-cilazaprilTablet5.0 mgOralMylan Pharmaceuticals2006-07-21Not applicableCanada
Mylan-cilazaprilTablet2.5 mgOralMylan Pharmaceuticals2006-07-21Not applicableCanada
Ntp-cilazaprilTablet2.5 mgOralTevaNot applicableNot applicableCanada
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Apo-cilazapril/hctzCilazapril (5 mg) + Hydrochlorothiazide (12.5 mg)TabletOralApotex Corporation2006-08-23Not applicableCanada
Inhibace PlusCilazapril (5 mg) + Hydrochlorothiazide (12.5 mg)TabletOralHoffmann La Roche1999-04-01Not applicableCanada
Teva-cilazapril/hctzCilazapril (5 mg) + Hydrochlorothiazide (12.5 mg)TabletOralTeva2009-03-30Not applicableCanada
International/Other Brands
Dynorm (Roche) / Inhibace (Roche) / Inhibestril (Teva) / Vascace (Roche) / Zapril (Mylan) / Zobox (Hemofarm)
Categories
UNII
8Q9454114Q
CAS number
88768-40-5
Weight
Average: 417.4986
Monoisotopic: 417.226371117
Chemical Formula
C22H31N3O5
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

Pharmacology

Indication

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

Associated Conditions
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
Human
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
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%.

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.

Affected organisms
Not Available
Pathways
PathwayCategory
Cilazapril Action PathwayDrug action
Cilazapril Metabolism PathwayDrug metabolism
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 Cilazapril.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Cilazapril.
AbacavirThe serum concentration of Abacavir can be decreased when it is combined with Cilazapril.
AcebutololAcebutolol may increase the hypotensive activities of Cilazapril.
AceclofenacThe risk or severity of adverse effects can be increased when Aceclofenac is combined with Cilazapril.
AcemetacinThe therapeutic efficacy of Cilazapril can be decreased when used in combination with Acemetacin.
Acetylsalicylic acidThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Acetylsalicylic acid is combined with Cilazapril.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Cilazapril.
AlclofenacThe risk or severity of adverse effects can be increased when Alclofenac is combined with Cilazapril.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Cilazapril.
Food Interactions
  • Food decreases cilazapril absorption with no significant clinical impact.
  • Take without regard to meals.

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. [PubMed:2434790]
External Links
Human Metabolome Database
HMDB0015433
KEGG Drug
D07699
PubChem Compound
56330
PubChem Substance
46505231
ChemSpider
50831
ChEBI
3698
ChEMBL
CHEMBL515606
Therapeutic Targets Database
DAP000912
PharmGKB
PA164748302
Drugs.com
Drugs.com Drug Page
Wikipedia
Cilazapril
ATC Codes
C09BA08 — Cilazapril and diureticsC09AA08 — Cilazapril
AHFS Codes
  • 24:32.04 — Angiotensin-converting Enzyme Inhibitors
FDA label
Download (114 KB)
MSDS
Download (81.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
Not AvailableUnknown StatusTreatmentIgA Glomerulonephritis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral5 mg
TabletOral
TabletOral1 mg
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)
US20060293517No2004-03-082024-03-08Us

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
logP-0.0079ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)3.41ChemAxon
pKa (Strongest Basic)5.35ChemAxon
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-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

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
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
Alpha-dipeptide / Alpha-amino acid ester / Alpha-amino acid or derivatives / 1,2-diazepane / Fatty acid ester / Diazepane / Aralkylamine / Dicarboxylic acid or derivatives / 1,2-diazinane / Pyridazine
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

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
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. [PubMed:10205231]
  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. [PubMed:10398211]
  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. [PubMed:10446934]
  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. [PubMed:1382157]
  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. [PubMed:1382161]
  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. [PubMed:18423812]
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Transporters

Kind
Protein
Organism
Human
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. [PubMed:11895100]
Kind
Protein
Organism
Human
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. [PubMed:18713951]
Kind
Protein
Organism
Human
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. [PubMed:18713951]

Drug created on June 30, 2007 12:09 / Updated on September 23, 2018 19:37