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Identification
NameCilazapril
Accession NumberDB01340
TypeSmall Molecule
GroupsApproved
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
SynonymLanguageCode
CilazaprilGerman/French/SpanishINN
Cilazaprilum LatinINN
Prescription ProductsNot Available
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cilazapriltablet1 mgoralSanis Health IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Cilazapriltablet2.5 mgoralSanis Health IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Over the Counter ProductsNot Available
International Brands
NameCompany
DynormRoche
InhibaceRoche
InhibestrilTeva
VascaceRoche
ZaprilMylan
ZoboxHemofarm
Brand mixtures
Brand NameIngredients
Dynorm PlusCilazapril and Hydrochlorothiazide
Inhibace plusCilazapril and Hydrochlorothiazide
Initiss PlusCilazapril and Hydrochlorothiazide
Inocar Plus Cilazapril and Hydrochlorothiazide
Vascace PlusCilazapril and Hydrochlorothiazide
Salts
Name/CASStructureProperties
Cilazapril Hydrate
ThumbNot applicableDBSALT001097
Categories
CAS number92077-78-6
WeightAverage: 417.4986
Monoisotopic: 417.226371117
Chemical FormulaC22H31N3O5
InChI KeyHHHKFGXWKKUNCY-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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as alpha amino acid esters. These are ester derivatives of alpha amino acids.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentAlpha amino acid esters
Alternative Parents
Substituents
  • Alpha-amino acid ester
  • Phenylpropylamine
  • Aralkylamine
  • Fatty acid ester
  • Diazepane
  • 1,2-diazepane
  • Fatty acyl
  • Benzenoid
  • Pyridazine
  • Dicarboxylic acid or derivatives
  • 1,2-diazinane
  • Monocyclic benzene moiety
  • Carboxylic acid hydrazide
  • Carboxylic acid ester
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Secondary amine
  • Secondary aliphatic amine
  • Carboxylic acid
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationCilazapril is an ACE inhibtor class drug used in the treatment of hypertension and heart failure.
PharmacodynamicsCilazapril 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 actionCilazapril 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.
AbsorptionMaximum plasma concentrations of cilazaprilat are reached within two hours after administration of cilazapril.
Volume of distributionNot Available
Protein bindingMaximum 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
SubstrateEnzymesProduct
Cilazapril
Not Available
CilazaprilatDetails
Route of eliminationCilazaprilat is eliminated unchanged by the kidneys. The total urinary recovery of cilazaprilat after intravenous administration of 2.5 mg is 91%.
Half lifeHalf-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%.

ToxicityLimited 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 organismsNot Available
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 substrateNon-inhibitor0.7804
CYP450 2D6 substrateNon-inhibitor0.7503
CYP450 2C19 substrateNon-inhibitor0.816
CYP450 3A4 substrateNon-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
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral1 mg
Tabletoral2.5 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
CountryPatent NumberApprovedExpires (estimated)
United States200602935172004-03-082024-03-08
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point98 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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
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 Reference
  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
External Links
ATC CodesC09AA08
AHFS Codes
  • 24:32.04
PDB EntriesNot Available
FDA labelDownload (114 KB)
MSDSDownload (81.5 KB)
Interactions
Drug Interactions
Drug
Acetylsalicylic acidMay diminish the antihypertensive effect of ACE Inhibitors. They may also diminish other beneficial pharmacodynamic effects desired for the treatment of CHF. The effects are likely dose-related. 100 mg doses aspirin appear to cause no problems, whereas 300 mg doses appear to significantly affect ACE Inhibitor efficacy.
AlfuzosinMay enhance the hypotensive effect of Antihypertensives.
AliskirenMay enhance the hyperkalemic effect of ACE Inhibitors. Aliskiren may enhance the hypotensive effect of ACE Inhibitors. Aliskiren may enhance the nephrotoxic effect of ACE Inhibitors.
AllopurinolACE Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol.
AmifostineAntihypertensives may enhance the hypotensive effect of Amifostine.
AprotininMay diminish the antihypertensive effect of ACE Inhibitors.
AzathioprineACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine.
ButabarbitalMay enhance the hypotensive effect of Hypotensive Agents.
ButethalMay enhance the hypotensive effect of Hypotensive Agents.
CanagliflozinMay enhance the hyperkalemic effect of ACE Inhibitors. Canagliflozin may enhance the hypotensive effect of ACE Inhibitors.
DapoxetineMay enhance the orthostatic hypotensive effect of ACE Inhibitors.
DiazoxideMay enhance the hypotensive effect of Antihypertensives.
DuloxetineHypotensive Agents may enhance the orthostatic hypotensive effect of DULoxetine.
EplerenoneMay enhance the hyperkalemic effect of ACE Inhibitors.
EverolimusMay enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased.
HeparinMay enhance the hyperkalemic effect of ACE Inhibitors.
HeptabarbitalMay enhance the hypotensive effect of Hypotensive Agents.
HexobarbitalMay enhance the hypotensive effect of Hypotensive Agents.
IcatibantMay diminish the antihypertensive effect of ACE Inhibitors.
LithiumACE Inhibitors may increase the serum concentration of Lithium.
MethohexitalMay enhance the hypotensive effect of Hypotensive Agents.
MethylphenidateMay diminish the antihypertensive effect of Antihypertensives.
ObinutuzumabAntihypertensives may enhance the hypotensive effect of Obinutuzumab.
PentobarbitalMay enhance the hypotensive effect of Hypotensive Agents.
PentoxifyllineMay enhance the hypotensive effect of Antihypertensives.
PrimidoneMay enhance the hypotensive effect of Hypotensive Agents.
RisperidoneHypotensive Agents may enhance the hypotensive effect of RisperiDONE.
RituximabAntihypertensives may enhance the hypotensive effect of RiTUXimab.
Salicylate-sodiumMay diminish the antihypertensive effect of ACE Inhibitors. They may also diminish other beneficial pharmacodynamic effects desired for the treatment of CHF. The effects are likely dose-related. 100 mg doses aspirin appear to cause no problems, whereas 300 mg doses appear to significantly affect ACE Inhibitor efficacy.
SecobarbitalMay enhance the hypotensive effect of Hypotensive Agents.
SirolimusMay enhance the adverse/toxic effect of ACE Inhibitors.
TadalafilMay enhance the antihypertensive effect of Antihypertensives.
TemsirolimusMay enhance the adverse/toxic effect of ACE Inhibitors.
TizanidineMay enhance the hypotensive effect of ACE Inhibitors.
TolvaptanMay enhance the hyperkalemic effect of ACE Inhibitors.
TrimethoprimMay enhance the hyperkalemic effect of ACE Inhibitors.
VardenafilMay enhance the antihypertensive effect of Antihypertensives.
YohimbineMay diminish the antihypertensive effect of Antihypertensives.
Food Interactions
  • Food decreases cilazapril absorption with no significant clinical impact.
  • Take without regard to meals.

Targets

1. Angiotensin-converting enzyme

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Angiotensin-converting enzyme P12821 Details

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
  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
  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
  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
  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
  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. Epub 2008 Apr 18. Pubmed
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

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

2. Solute carrier family 15 member 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 15 member 1 P46059 Details

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. Epub 2008 Aug 19. Pubmed

3. Solute carrier family 15 member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 15 member 2 Q16348 Details

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. Epub 2008 Aug 19. Pubmed

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Drug created on June 30, 2007 12:09 / Updated on December 05, 2014 11:49