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Identification
NameSpirapril
Accession NumberDB01348
Typesmall molecule
Groupsapproved
Description

Spirapril is an ACE inhibitor antihypertensive drug used to treat hypertension. Like many ACE inhibitors, this is a prodrug which is converted to the active metabolite spiraprilat following oral administration. ACE inhibitors are used primarily in treatment of hypertension and congestive heart failure.

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
RenormaxNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number83647-97-6
WeightAverage: 466.614
Monoisotopic: 466.15961346
Chemical FormulaC22H30N2O5S2
InChI KeyInChIKey=HRWCVUIFMSZDJS-SZMVWBNQSA-N
InChI
InChI=1S/C22H30N2O5S2/c1-3-29-21(28)17(10-9-16-7-5-4-6-8-16)23-15(2)19(25)24-14-22(30-11-12-31-22)13-18(24)20(26)27/h4-8,15,17-18,23H,3,9-14H2,1-2H3,(H,26,27)/t15-,17-,18-/m0/s1
IUPAC Name
(8S)-7-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid
SMILES
CCOC(=O)[C@H](CCC1=CC=CC=C1)N[C@@H](C)C(=O)N1CC2(C[C@H]1C(O)=O)SCCS2
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; N-acyl-alpha Amino Acids; Alpha Amino Acid Amides; Phenylpropylamines; Pyrrolidine Carboxylic Acids; Dithioketals; Fatty Acid Esters; Dicarboxylic Acids and Derivatives; Tertiary Carboxylic Acid Amides; Dithiolanes; Carboxylic Acid Esters; Tertiary Amines; Ethers; Dialkylamines; Carboxylic Acids; Enolates; Polyamines; Thioethers
Substituentsn-acyl-alpha amino acid or derivative; alpha-amino acid ester; n-acyl-alpha-amino acid; alpha-amino acid amide; alpha-amino acid or derivative; phenylpropylamine; pyrrolidine carboxylic acid or derivative; pyrrolidine carboxylic acid; fatty acid ester; dithioketal; dicarboxylic acid derivative; benzene; tertiary carboxylic acid amide; thioacetal; pyrrolidine; dithiolane; tertiary amine; carboxamide group; carboxylic acid ester; polyamine; secondary amine; secondary aliphatic amine; carboxylic acid; thioether; enolate; ether; 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
IndicationSpirapril is an ACE inhibitor class drug used to treat hypertension.
PharmacodynamicsSpirapril is an angiotensin-converting enzyme (ACE) inhibitor. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. By blocking ACE, spirapril decreases angiotensin II which is a vasoconstrictor and inducer of aldosterone. So by inhibiting the enzymes, aldosterone secreation is decreased (so less sodium is reabsorbed) and there is a decrease in vasoconstriction. Combined, this leades to a decrease in blood pressure.
Mechanism of actionSpiraprilat, the active metabolite of spirapril, competes with angiotensin I for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II. As angiotensin II is a vasoconstrictor and a negative-feedback mediator for renin activity, lower concentrations result in a decrease in blood pressure and stimulation of baroreceptor reflex mechanisms, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Spiraprilat may also act on kininase II, an enzyme identical to ACE that degrades the vasodilator bradykinin.
AbsorptionBioavailability is 50% following oral administration.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic. Converted to spiraprilat following oral administration.

SubstrateEnzymesProduct
Spirapril
    SpiraprilatDetails
    Route of eliminationNot Available
    Half life30 to 35 hours
    ClearanceNot Available
    ToxicityNot Available
    Affected organisms
    • Humans and other mammals
    Pathways
    PathwayCategorySMPDB ID
    Spirapril Action PathwayDrug actionSMP00156
    Spirapril Metabolism PathwayDrug metabolismSMP00598
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption - 0.5287
    Blood Brain Barrier - 0.9614
    Caco-2 permeable - 0.83
    P-glycoprotein substrate Substrate 0.8223
    P-glycoprotein inhibitor I Non-inhibitor 0.6938
    P-glycoprotein inhibitor II Non-inhibitor 0.7426
    Renal organic cation transporter Non-inhibitor 0.8836
    CYP450 2C9 substrate Non-substrate 0.833
    CYP450 2D6 substrate Non-substrate 0.8553
    CYP450 3A4 substrate Non-substrate 0.5658
    CYP450 1A2 substrate Non-inhibitor 0.8439
    CYP450 2C9 substrate Non-inhibitor 0.7259
    CYP450 2D6 substrate Non-inhibitor 0.8813
    CYP450 2C19 substrate Non-inhibitor 0.5956
    CYP450 3A4 substrate Inhibitor 0.5073
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6331
    Ames test Non AMES toxic 0.8764
    Carcinogenicity Non-carcinogens 0.908
    Biodegradation Not ready biodegradable 0.9115
    Rat acute toxicity 2.2396 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.9961
    hERG inhibition (predictor II) Non-inhibitor 0.5579
    Pharmacoeconomics
    Manufacturers
    • Schering corp
    PackagersNot Available
    Dosage formsNot Available
    PricesNot Available
    PatentsNot Available
    Properties
    Statesolid
    Experimental PropertiesNot Available
    Predicted Properties
    PropertyValueSource
    water solubility2.93e-02 g/lALOGPS
    logP1.79ALOGPS
    logP1.6ChemAxon
    logS-4.2ALOGPS
    pKa (strongest acidic)3.62ChemAxon
    pKa (strongest basic)5.2ChemAxon
    physiological charge-1ChemAxon
    hydrogen acceptor count5ChemAxon
    hydrogen donor count2ChemAxon
    polar surface area95.94ChemAxon
    rotatable bond count10ChemAxon
    refractivity121.94ChemAxon
    polarizability48.74ChemAxon
    number of rings3ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleYesChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis ReferenceNot Available
    General Reference
    1. 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
    2. Noble S, Sorkin EM: Spirapril. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension. Drugs. 1995 May;49(5):750-66. Pubmed
    3. 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
    4. Shohat J, Wittenberg C, Erman A, Rosenfeld J, Boner G: Acute and chronic effects of spirapril, alone or in combination with isradipine on kidney function and blood pressure in patients with reduced kidney function and hypertension. Scand J Urol Nephrol. 1999 Feb;33(1):57-62. Pubmed
    External Links
    ResourceLink
    PubChem Compound5311447
    PubChem Substance46506126
    ChemSpider4470933
    BindingDB50017124
    Therapeutic Targets DatabaseDAP000911
    PharmGKBPA164776913
    WikipediaSpirapril
    ATC CodesC09AA11
    AHFS CodesNot Available
    PDB EntriesNot Available
    FDA labelNot Available
    MSDSNot Available
    Interactions
    Drug Interactions
    Drug
    AmilorideIncreased risk of hyperkalemia
    LithiumThe ACE inhibitor increases serum levels of lithium
    PotassiumIncreased risk of hyperkalemia
    TizanidineTizanidine increases the risk of hypotension with the ACE inhibitor
    TriamtereneIncreased risk of hyperkalemia
    Food Interactions
    • Avoid alcohol.
    • Do not take calcium, aluminum, magnesium or iron supplements within 2 hours of taking this medication.
    • Herbs that may attenuate the antihypertensive effect of spirapril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
    • High salt intake may attenuate the antihypertensive effect of spirapril.
    • Spirapril 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. 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
    2. Maul B, Krause W, Pankow K, Becker M, Gembardt F, Alenina N, Walther T, Bader M, Siems WE: Central angiotensin II controls alcohol consumption via its AT1 receptor. FASEB J. 2005 Sep;19(11):1474-81. Pubmed
    3. Hermida RC, Ayala DE, Fontao MJ, Mojon A, Alonso I, Fernandez JR: Administration-time-dependent effects of spirapril on ambulatory blood pressure in uncomplicated essential hypertension. Chronobiol Int. 2010 May;27(3):560-74. Pubmed
    4. Arend U, Albrecht S, Meisel E, Schmidt J: [Influence of ACE inhibitor spirapril on left ventricular hypertrophy] Fortschr Med Orig. 2002 Dec 5;120(4):147-50. Pubmed
    5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. 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 30, 2007 12:15 / Updated on September 16, 2013 17:14