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Identification
NameQuinapril
Accession NumberDB00881  (APRD00523)
Typesmall molecule
Groupsapproved, investigational
Description

Quinapril is a prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is metabolized to quinaprilat (quinapril diacid) following oral administration. Quinaprilat is a competitive inhibitor of 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). Quinapril may be used to treat essential hypertension and congestive heart failure.

Structure
Thumb
Synonyms
SynonymLanguageCode
QuinaprilumLatinNot Available
Salts
Name/CAS Structure Properties
Quinapril Hydrochloride
82586-55-8
Thumb
  • InChI Key: IBBLRJGOOANPTQ-JKVLGAQCSA-N
  • Monoisotopic Mass: 474.192149819
  • Average Mass: 474.977
DBSALT000465
Brand names
NameCompany
AccuprilPfizer
AccuprinPfizer (Italy)
AccuproPfizer (Austria, Denmark, Finland, Germany, Hungary, Ireland, Sweden, Switzerland, United Kingdom, Ukraine), Godecke (Czech Republic, Germany, Poland, Russia), Parke, Davis (Germany)
AcequinNot Available
AcuitelNot Available
KorecNot Available
QuinazilNot Available
Brand mixtures
Brand NameIngredients
Accupro Compquinapril hydrochloride + hydrochlorothiazide
Accureticquinapril hydrochloride + hydrochlorothiazide
Accuzidequinapril hydrochloride + hydrochlorothiazide
Acequidequinapril hydrochloride + hydrochlorothiazide
Acuilixquinapril hydrochloride + hydrochlorothiazide
Bicetilquinapril hydrochloride + hydrochlorothiazide
Co-Quinaprilquinapril hydrochloride + hydrochlorothiazide
Koreticquinapril hydrochloride + hydrochlorothiazide
Lidaltrin Diuquinapril hydrochloride + hydrochlorothiazide
Quimeaquinapril hydrochloride + hydrochlorothiazide
QuinaLich compquinapril hydrochloride + hydrochlorothiazide
Quinaplusquinapril hydrochloride + hydrochlorothiazide
Quinapril compquinapril hydrochloride + hydrochlorothiazide
Quinareticquinapril hydrochloride + hydrochlorothiazide
Quinazidequinapril hydrochloride + hydrochlorothiazide
Quiril Compquinapril hydrochloride + hydrochlorothiazide
Stadapressquinapril hydrochloride + hydrochlorothiazide
Categories
CAS number85441-61-8
WeightAverage: 438.5161
Monoisotopic: 438.21547208
Chemical FormulaC25H30N2O5
InChI KeyInChIKey=JSDRRTOADPPCHY-HSQYWUDLSA-N
InChI
InChI=1S/C25H30N2O5/c1-3-32-25(31)21(14-13-18-9-5-4-6-10-18)26-17(2)23(28)27-16-20-12-8-7-11-19(20)15-22(27)24(29)30/h4-12,17,21-22,26H,3,13-16H2,1-2H3,(H,29,30)/t17-,21-,22-/m0/s1
IUPAC Name
(3S)-2-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
SMILES
CCOC(=O)[C@H](CCC1=CC=CC=C1)N[C@@H](C)C(=O)N1CC2=CC=CC=C2C[C@H]1C(O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentPeptides
Alternative parentsAlpha Amino Acid Esters; Alpha Amino Acid Amides; Isoquinolines and Derivatives; Phenylpropylamines; Fatty Acid Esters; Dicarboxylic Acids and Derivatives; Tertiary Carboxylic Acid Amides; Tertiary Amines; Carboxylic Acid Esters; Carboxylic Acids; Dialkylamines; Polyamines; Enolates; Ethers
Substituentsalpha-amino acid ester; alpha-amino acid amide; alpha-amino acid or derivative; isoquinoline; phenylpropylamine; fatty acid ester; benzene; dicarboxylic acid derivative; tertiary carboxylic acid amide; carboxamide group; tertiary amine; carboxylic acid ester; secondary aliphatic amine; secondary amine; polyamine; ether; enolate; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the peptides. These are compounds containing an amide derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another.
Pharmacology
IndicationFor the treatment of hypertension and as adjunct therapy in the treatment of congestive heart failure. May also be used to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.
PharmacodynamicsQuinapril is a nonpeptide, non-sulfhydryl prodrug that is deesterified to quinaprilat (quinapril diacid), its major active metabolite following oral administration. Quinaprilat lowers blood pressure by antagonizing the effect 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 using 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 sustain the effects of quinaprilat by causing increased vasodilation and decreased blood pressure.
Mechanism of actionThere 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. Quinaprilat, the principle active metabolite of quinapril, 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. Quinaprilat 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.
AbsorptionPeak plasma concentrations of quinapril occur within one hour following oral administration. The extent of absorption is at least 60%. The rate and extent of quinapril absorption are diminished moderately (approximately 25-30%) when ACCUPRIL tablets are administered during a high-fat meal.
Volume of distributionNot Available
Protein binding97%
Metabolism

Hepatic.

SubstrateEnzymesProduct
Quinapril
    QuinaprilatDetails
    Route of eliminationQuinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose
    Half lifeElimination half life is 2 hours with a prolonged terminal phase of 25 hours.
    ClearanceNot Available
    ToxicityOverdose may lead to severe hypotension. LD50=1739mg/kg (orally in mice). The most common adverse effects observed in controlled clinical trials were dizziness, cough, chest pain, dyspnea, fatigue, and nausea/vomiting.
    Affected organisms
    • Humans and other mammals
    Pathways
    PathwayCategorySMPDB ID
    Quinapril Action PathwayDrug actionSMP00153
    Quinapril Metabolism PathwayDrug metabolismSMP00596
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.5597
    Blood Brain Barrier - 0.9409
    Caco-2 permeable - 0.8208
    P-glycoprotein substrate Substrate 0.8895
    P-glycoprotein inhibitor I Inhibitor 0.7344
    P-glycoprotein inhibitor II Inhibitor 0.5869
    Renal organic cation transporter Non-inhibitor 0.8258
    CYP450 2C9 substrate Non-substrate 0.8594
    CYP450 2D6 substrate Non-substrate 0.8412
    CYP450 3A4 substrate Substrate 0.5356
    CYP450 1A2 substrate Non-inhibitor 0.8597
    CYP450 2C9 substrate Non-inhibitor 0.6832
    CYP450 2D6 substrate Non-inhibitor 0.8636
    CYP450 2C19 substrate Non-inhibitor 0.6016
    CYP450 3A4 substrate Inhibitor 0.5347
    CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5162
    Ames test Non AMES toxic 0.9091
    Carcinogenicity Non-carcinogens 0.9294
    Biodegradation Not ready biodegradable 0.9596
    Rat acute toxicity 2.2690 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.9763
    hERG inhibition (predictor II) Inhibitor 0.7176
    Pharmacoeconomics
    Manufacturers
    • Pfizer pharmaceuticals ltd
    • Actavis totowa llc
    • Apotex inc
    • Genpharm inc
    • Invagen pharmaceuticals inc
    • Lupin ltd
    • Mylan pharmaceuticals inc
    • Ranbaxy laboratories ltd
    • Sandoz inc
    • Sun pharmaceutical industries ltd
    • Teva pharmaceuticals usa inc
    • Watson laboratories inc florida
    Packagers
    Dosage forms
    FormRouteStrength
    Tablet, film coatedOral10 mg
    Tablet, film coatedOral20 mg
    Tablet, film coatedOral40 mg
    Tablet, film coatedOral5 mg
    Prices
    Unit descriptionCostUnit
    Accupril 10 mg tablet2.02USDtablet
    Accupril 20 mg tablet2.02USDtablet
    Accupril 40 mg tablet2.02USDtablet
    Accupril 5 mg tablet2.02USDtablet
    Quinapril 10 mg tablet1.57USDtablet
    Quinapril 20 mg tablet1.57USDtablet
    Quinapril 40 mg tablet1.57USDtablet
    Quinapril 5 mg tablet1.57USDtablet
    Quinapril HCl 10 mg tablet1.27USDtablet
    Quinapril HCl 20 mg tablet1.27USDtablet
    Quinapril HCl 40 mg tablet1.27USDtablet
    Quinapril HCl 5 mg tablet1.27USDtablet
    Quinaretic 10-12.5 mg tablet1.27USDtablet
    Quinaretic 20-12.5 mg tablet1.27USDtablet
    Quinaretic 20-25 mg tablet1.27USDtablet
    Accupril 10 mg Tablet0.96USDtablet
    Accupril 20 mg Tablet0.96USDtablet
    Accupril 40 mg Tablet0.96USDtablet
    Accupril 5 mg Tablet0.96USDtablet
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    United States56840161995-05-042015-05-04
    Canada20230892003-01-142010-08-10
    Canada13316151994-08-232011-08-23
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    melting point120-130 °CNot Available
    water solubility1 mg/LNot Available
    logP3.2Not Available
    Predicted Properties
    PropertyValueSource
    water solubility8.50e-03 g/lALOGPS
    logP1.39ALOGPS
    logP1.96ChemAxon
    logS-4.7ALOGPS
    pKa (strongest acidic)3.7ChemAxon
    pKa (strongest basic)5.2ChemAxon
    physiological charge-1ChemAxon
    hydrogen acceptor count5ChemAxon
    hydrogen donor count2ChemAxon
    polar surface area95.94ChemAxon
    rotatable bond count10ChemAxon
    refractivity119.96ChemAxon
    polarizability47.36ChemAxon
    number of rings3ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleYesChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    Om P. Goel, Uldis Krolls, “Crystalline quinapril and a process for producing the same.” U.S. Patent US4761479, issued August, 1982.

    US4761479
    General Reference
    1. Khan BV, Sola S, Lauten WB, Natarajan R, Hooper WC, Menon RG, Lerakis S, Helmy T: Quinapril, an ACE inhibitor, reduces markers of oxidative stress in the metabolic syndrome. Diabetes Care. 2004 Jul;27(7):1712-5. Pubmed
    2. Kieback AG, Felix SB, Reffelmann T: Quinaprilat: a review of its pharmacokinetics, pharmacodynamics, toxicological data and clinical application. Expert Opin Drug Metab Toxicol. 2009 Oct;5(10):1337-47. Pubmed
    3. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, Bass T, Pepine C, Texter M, Haber H, Uprichard A, Cashin-Hemphill L, Lees RS: The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001 May 1;87(9):1058-63. Pubmed
    4. Tsikouris JP, Suarez JA, Meyerrose GE, Ziska M, Fike D, Smith J: Questioning a class effect: does ACE inhibitor tissue penetration influence the degree of fibrinolytic balance alteration following an acute myocardial infarction? J Clin Pharmacol. 2004 Feb;44(2):150-7. Pubmed
    5. Valles Prats M, Matas Serra M, Bronsoms Artero J, Mate Benito G, Torguet Escuder P, Mauri Nicolas JM: Quinapril ACE-inhibition effects on adrenergic parameters in moderate essential hypertension. Kidney Int Suppl. 1996 Jun;55:S104-6. Pubmed
    6. Voors AA, van Geel PP, Oosterga M, Buikema H, van Veldhuisen DJ, van Gilst WH: Vascular effects of quinapril completely depend on ACE insertion/deletion polymorphism. J Renin Angiotensin Aldosterone Syst. 2004 Sep;5(3):130-4. Pubmed
    7. Yamada S, Muraoka I, Kato K, Hiromi Y, Takasu R, Seno H, Kawahara H, Nabeshima T: Elimination kinetics of quinaprilat and perindoprilat in hypertensive patients with renal failure on haemodialysis. Biol Pharm Bull. 2003 Jun;26(6):872-5. Pubmed
    External Links
    ResourceLink
    KEGG DrugD03752
    KEGG CompoundC07398
    PubChem Compound54892
    PubChem Substance46506309
    ChemSpider49565
    ChEBI8713
    ChEMBLCHEMBL1592
    Therapeutic Targets DatabaseDAP000588
    PharmGKBPA451205
    Drug Product Database1947672
    RxListhttp://www.rxlist.com/cgi/generic/quinap.htm
    Drugs.comhttp://www.drugs.com/cdi/quinapril.html
    PDRhealthhttp://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=Acc1002.html&contentName=Accupril&contentId=03
    WikipediaQuinapril
    ATC CodesC09AA06
    AHFS Codes
    • 24:32.04
    PDB Entries
    FDA labelNot Available
    MSDSNot Available
    Interactions
    Drug Interactions
    Drug
    AmilorideIncreased risk of hyperkalemia
    Azilsartan medoxomilPharmacodynamic synergism: dual blockade of renin-angiotensin system. Increases risks of hypotension, hyperkalemia, renal impairment.
    DrospirenoneIncreased risk of hyperkalemia
    IcatibantIcatibant may attenuate the antihypertensive effect of ACE inhibitors by pharmacodynamic antagonism. Monitor concomitant therapy closely.
    LithiumThe ACE inhibitor increases serum levels of lithium
    PotassiumIncreased risk of hyperkalemia
    SpironolactoneIncreased risk of hyperkalemia
    TetracyclineQuinapril may decrease the absorption of tetracycline.
    TizanidineTizanidine increases the risk of hypotension with the ACE inhibitor
    TobramycinIncreased risk of nephrotoxicity
    TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
    TriamtereneIncreased risk of hyperkalemia
    TrovafloxacinQuinapril may decrease the absorption of orally administered Trovafloxacin. The Quinapril formulation contains magnesium ions that may intefere with Trovafloxacin absorption. Administer Trovafloxacin 2 hours before or 6 hours after the Quinapril dose to minimize the interaction.
    Food Interactions
    • Do not take with a high-fat meal.
    • Herbs that may attenuate the antihypertensive effect of quinapril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
    • High salt intake may attenuate the antihypertensive effect of quinapril.
    • Quinapril may decrease the excretion of potassium. Salt substitutes containing potassium may increase the risk of hyperkalemia.

    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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
    2. Culy CR, Jarvis B: Quinapril: a further update of its pharmacology and therapeutic use in cardiovascular disorders. Drugs. 2002;62(2):339-85. Pubmed
    3. Klutchko S, Blankley CJ, Fleming RW, Hinkley JM, Werner AE, Nordin I, Holmes A, Hoefle ML, Cohen DM, Essenburg AD, et al.: Synthesis of novel angiotensin converting enzyme inhibitor quinapril and related compounds. A divergence of structure-activity relationships for non-sulfhydryl and sulfhydryl types. J Med Chem. 1986 Oct;29(10):1953-61. Pubmed
    4. Song JC, White CM: Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet. 2002;41(3):207-24. Pubmed

    1. 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

    2. 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 13, 2005 07:24 / Updated on September 16, 2013 17:12