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Identification
NameCilazapril
Accession NumberDB01340
Typesmall molecule
Groupsapproved
Description

One of the angiotensin-converting enzyme inhibitors (ACE inhibitors) used for hypertension. It is a prodrug that is hydrolyzed after absorption to its main metabolite cilazaprilat. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
InhibaceNot AvailableNot Available
SaltsNot Available
Brand namesNot Available
Brand mixturesNot Available
Categories
CAS number92077-78-6
WeightAverage: 417.4986
Monoisotopic: 417.226371117
Chemical FormulaC22H31N3O5
InChI KeyInChIKey=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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentAlpha Amino Acid Esters
Alternative parentsPhenylpropylamines; Fatty Acid Esters; Diazinanes; Pyridazines and Derivatives; Dicarboxylic Acids and Derivatives; Carboxylic Acid Esters; Carboxylic Acid Hydrazides; Enolates; Ethers; Dialkylamines; Polyamines; Carboxylic Acid Amides; Carboxylic Acids; Hydrazines and Derivatives
Substituentsphenylpropylamine; fatty acid ester; 1,2-diazinane; dicarboxylic acid derivative; benzene; pyridazine; carboxylic acid ester; carboxamide group; carboxylic acid hydrazide; secondary aliphatic amine; polyamine; secondary amine; enolate; ether; carboxylic acid; hydrazine derivative; organonitrogen compound; amine
Classification descriptionThis compound belongs to the alpha amino acid esters. These are ester derivatives of alpha amino acids.
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.
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.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
SubstrateEnzymesProduct
Cilazapril
    CilazaprilatDetails
    Route of eliminationNot Available
    Half lifeNot Available
    ClearanceNot Available
    ToxicityNot Available
    Affected organismsNot Available
    Pathways
    PathwayCategorySMPDB ID
    Cilazapril Action PathwayDrug actionSMP00147
    Cilazapril Metabolism PathwayDrug metabolismSMP00592
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.9157
    Blood Brain Barrier - 0.9402
    Caco-2 permeable - 0.7698
    P-glycoprotein substrate Substrate 0.8727
    P-glycoprotein inhibitor I Inhibitor 0.7775
    P-glycoprotein inhibitor II Non-inhibitor 0.8788
    Renal organic cation transporter Non-inhibitor 0.8318
    CYP450 2C9 substrate Non-substrate 0.7876
    CYP450 2D6 substrate Non-substrate 0.8283
    CYP450 3A4 substrate Substrate 0.5396
    CYP450 1A2 substrate Non-inhibitor 0.882
    CYP450 2C9 substrate Non-inhibitor 0.7804
    CYP450 2D6 substrate Non-inhibitor 0.7503
    CYP450 2C19 substrate Non-inhibitor 0.816
    CYP450 3A4 substrate Non-inhibitor 0.8201
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8376
    Ames test Non AMES toxic 0.6023
    Carcinogenicity Non-carcinogens 0.9028
    Biodegradation Not ready biodegradable 0.9942
    Rat acute toxicity 2.3700 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.9311
    hERG inhibition (predictor II) Inhibitor 0.6303
    Pharmacoeconomics
    ManufacturersNot Available
    PackagersNot Available
    Dosage forms
    FormRouteStrength
    TabletOral
    Prices
    Unit descriptionCostUnit
    Inhibace 5 mg Tablet0.94USDtablet
    Inhibace 2.5 mg Tablet0.81USDtablet
    Inhibace 1 mg Tablet0.7USDtablet
    Apo-Cilazapril 5 mg Tablet0.52USDtablet
    Co Cilazapril 5 mg Tablet0.52USDtablet
    Mylan-Cilazapril 5 mg Tablet0.52USDtablet
    Novo-Cilazapril 5 mg Tablet0.52USDtablet
    Pms-Cilazapril 5 mg Tablet0.52USDtablet
    Apo-Cilazapril 2.5 mg Tablet0.45USDtablet
    Co Cilazapril 2.5 mg Tablet0.45USDtablet
    Mylan-Cilazapril 2.5 mg Tablet0.45USDtablet
    Novo-Cilazapril 2.5 mg Tablet0.45USDtablet
    Pms-Cilazapril 2.5 mg Tablet0.45USDtablet
    Apo-Cilazapril 1 mg Tablet0.39USDtablet
    Mylan-Cilazapril 1 mg Tablet0.39USDtablet
    Novo-Cilazapril 1 mg Tablet0.39USDtablet
    Pms-Cilazapril 1 mg Tablet0.39USDtablet
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    PatentsNot Available
    Properties
    Statesolid
    Experimental PropertiesNot Available
    Predicted Properties
    PropertyValueSource
    water solubility1.06e+00 g/lALOGPS
    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 area99.18ChemAxon
    rotatable bond count9ChemAxon
    refractivity110.56ChemAxon
    polarizability44.73ChemAxon
    number of rings3ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleYesChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    Yatendra Kumar, Mohan Prasad, Kaptan Singh, Kintali Ramana, Surendra Dhingra, “Enantiomerically pure cilazapril, process for preparation.” U.S. Patent US20060293517, issued December 28, 2006.

    US20060293517
    General ReferenceNot Available
    External Links
    ResourceLink
    Therapeutic Targets DatabaseDAP000912
    PharmGKBPA164748302
    Drug Product Database1911465
    WikipediaCilazapril
    ATC CodesC09AA08
    AHFS Codes
    • 24:32.04
    PDB EntriesNot Available
    FDA labelNot Available
    MSDSNot Available
    Interactions
    Drug Interactions
    Drug
    AmilorideIncreased risk of hyperkalemia
    DrospirenoneIncreased risk of hyperkalemia
    LithiumThe ACE inhibitor increases serum levels of lithium
    PotassiumIncreased risk of hyperkalemia
    SpironolactoneIncreased risk of hyperkalemia
    TizanidineTizanidine increases the risk of hypotension with the ACE inhibitor
    TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
    TriamtereneIncreased risk of hyperkalemia
    Food Interactions
    • Food decreases cilazapril absorption with no significant clinical impact.
    • Take without regard to meals.

    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

    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

    Comments
    Drug created on June 30, 2007 12:09 / Updated on September 16, 2013 17:14