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Identification
NameFosinopril
Accession NumberDB00492  (APRD00526)
Typesmall molecule
Groupsapproved
Description

Fosinopril is a phosphinic acid-containing ester prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is rapidly hydrolyzed to fosinoprilat, its principle active metabolite. Fosinoprilat inhibits 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). Fosinopril may be used to treat mild to moderate hypertension, as an adjunct in the treatment of congestive heart failure, and to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.

Structure
Thumb
SynonymsNot Available
Salts
Name/CAS Structure Properties
Fosinopril Sodium
88889-14-9
Thumb
  • InChI Key: TVTJZMHAIQQZTL-HREVRLCXSA-M
  • Monoisotopic Mass: 585.283133986
  • Average Mass: 585.6443
DBSALT000193
Brand names
NameCompany
AcecorSPA (Czech Republic)
MonoprilBristol-Myers Squibb
StarilBMS (United Kingdom)
Brand mixtures
Brand NameIngredients
Monopril-HCTfosinopril sodium + hydrochlorothiazide
CategoriesNot Available
CAS number98048-97-6
WeightAverage: 563.6625
Monoisotopic: 563.301189343
Chemical FormulaC30H46NO7P
InChI KeyInChIKey=BIDNLKIUORFRQP-FKDWWROVSA-N
InChI
InChI=1S/C30H46NO7P/c1-4-28(33)37-30(22(2)3)38-39(36,18-12-11-15-23-13-7-5-8-14-23)21-27(32)31-20-25(19-26(31)29(34)35)24-16-9-6-10-17-24/h5,7-8,13-14,22,24-26,30H,4,6,9-12,15-21H2,1-3H3,(H,34,35)/t25-,26+,30?,39?/m1/s1
IUPAC Name
(2S,4S)-4-cyclohexyl-1-(2-{[2-methyl-1-(propanoyloxy)propoxy](4-phenylbutyl)phosphoryl}acetyl)pyrrolidine-2-carboxylic acid
SMILES
CCC(=O)OC(OP(=O)(CCCCC1=CC=CC=C1)CC(=O)N1C[C@@H](C[C@H]1C(O)=O)C1CCCCC1)C(C)C
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentN-acyl-alpha Amino Acids
Alternative parentsPyrrolidine Carboxylic Acids; Dicarboxylic Acids and Derivatives; Benzene and Substituted Derivatives; Tertiary Carboxylic Acid Amides; Tertiary Amines; Carboxylic Acid Esters; Polyamines; Carboxylic Acids; Enolates; Ethers
Substituentspyrrolidine carboxylic acid; pyrrolidine carboxylic acid or derivative; benzene; dicarboxylic acid derivative; pyrrolidine; tertiary carboxylic acid amide; carboxylic acid ester; carboxamide group; tertiary amine; polyamine; enolate; ether; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the n-acyl-alpha amino acids. These are compounds containing an alpha amino acid which bears an acyl group at his terminal nitrogen atom.
Pharmacology
IndicationFor treating mild to moderate hypertension, use as an adjunct in treating congestive heart failure, and may be used to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.
PharmacodynamicsFollowing oral administration, fosinopril is rapidly and completely hydrolyzed to its principle active metabolite, fosinoprilat. Hydrolysis is thought to occur in the gastrointestinal mucosa and liver. Fosinoprilat is a competitive inhibitor of ACE, a peptidyl dipeptidase that is part 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 further sustain the effects of fosinoprilat 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. Fosinoprilat, the active metabolite of fosinopril, 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. Fosinoprilat 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.
AbsorptionAverage absolute absorption is 36%. The primary site of absorption is the proximal small intestine (duodenum/jejunum). Food slows the rate of absorption with no effect on the extent of absorption.
Volume of distributionNot Available
Protein bindingFosinoprilat is ≥95% protein bound
Metabolism

Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites.

SubstrateEnzymesProduct
Fosinopril
    FosinoprilatDetails
    Route of eliminationAfter oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces.
    Half life12 hours
    Clearance
    • 26 – 39 mL/min [healthy]
    ToxicityHuman overdoses of fosinopril have not been reported, but the most common manifestation of human fosinopril overdosage is likely to be hypotension. Oral doses of fosinopril at 2600 mg/kg in rats were associated with significant lethality. The most common adverse effects include dizzines, cough, fatigue, and headache.
    Affected organisms
    • Humans and other mammals
    Pathways
    PathwayCategorySMPDB ID
    Fosinopril Action PathwayDrug actionSMP00149
    Fosinopril Metabolism PathwayDrug metabolismSMP00594
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.9532
    Blood Brain Barrier - 0.667
    Caco-2 permeable - 0.6561
    P-glycoprotein substrate Substrate 0.6165
    P-glycoprotein inhibitor I Inhibitor 0.7161
    P-glycoprotein inhibitor II Non-inhibitor 0.6774
    Renal organic cation transporter Non-inhibitor 0.812
    CYP450 2C9 substrate Non-substrate 0.7028
    CYP450 2D6 substrate Non-substrate 0.8128
    CYP450 3A4 substrate Substrate 0.6729
    CYP450 1A2 substrate Non-inhibitor 0.8913
    CYP450 2C9 substrate Non-inhibitor 0.7438
    CYP450 2D6 substrate Non-inhibitor 0.9004
    CYP450 2C19 substrate Non-inhibitor 0.5725
    CYP450 3A4 substrate Non-inhibitor 0.7303
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6376
    Ames test Non AMES toxic 0.7141
    Carcinogenicity Non-carcinogens 0.8025
    Biodegradation Not ready biodegradable 0.8102
    Rat acute toxicity 2.8211 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.9534
    hERG inhibition (predictor II) Non-inhibitor 0.5918
    Pharmacoeconomics
    Manufacturers
    • Apotex inc etobicoke site
    • Invagen pharmaceuticals inc
    • Ranbaxy laboratories ltd
    • Sandoz inc
    • Teva pharmaceuticals usa inc
    • Watson laboratories inc
    • Watson laboratories inc florida
    • Bristol myers squibb co pharmaceutical research institute
    Packagers
    Dosage forms
    FormRouteStrength
    TabletOral10 mg
    TabletOral20 mg
    TabletOral40 mg
    Prices
    Unit descriptionCostUnit
    Monopril HCT 10-12.5 mg tablet1.71USDtablet
    Monopril 10 mg tablet1.68USDtablet
    Monopril 40 mg tablet1.67USDtablet
    Monopril 20 mg tablet1.62USDtablet
    Fosinopril Sodium-HCTZ 10-12.5 mg tablet1.61USDtablet
    Fosinopril Sodium-HCTZ 20-12.5 mg tablet1.61USDtablet
    Fosinopril sodium 20 mg tablet1.25USDtablet
    Fosinopril sodium 40 mg tablet1.25USDtablet
    Fosinopril sodium 10 mg tablet1.21USDtablet
    Monopril 20 mg Tablet1.1USDtablet
    Monopril 10 mg Tablet0.91USDtablet
    Apo-Fosinopril 20 mg Tablet0.61USDtablet
    Fosinopril 20 mg Tablet0.61USDtablet
    Jamp-Fosinopril 20 mg Tablet0.61USDtablet
    Mylan-Fosinopril 20 mg Tablet0.61USDtablet
    Novo-Fosinopril 20 mg Tablet0.61USDtablet
    Ran-Fosinopril 20 mg Tablet0.61USDtablet
    Apo-Fosinopril 10 mg Tablet0.51USDtablet
    Fosinopril 10 mg Tablet0.51USDtablet
    Jamp-Fosinopril 10 mg Tablet0.51USDtablet
    Mylan-Fosinopril 10 mg Tablet0.51USDtablet
    Novo-Fosinopril 10 mg Tablet0.51USDtablet
    Ran-Fosinopril 10 mg Tablet0.51USDtablet
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    United States50063441993-01-102010-01-10
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    melting point149-153 °CNot Available
    water solubilityInsolubleNot Available
    logP6.3Not Available
    Predicted Properties
    PropertyValueSource
    water solubility1.01e-03 g/lALOGPS
    logP4.71ALOGPS
    logP5.49ChemAxon
    logS-5.8ALOGPS
    pKa (strongest acidic)3.87ChemAxon
    pKa (strongest basic)-4.4ChemAxon
    physiological charge-1ChemAxon
    hydrogen acceptor count5ChemAxon
    hydrogen donor count1ChemAxon
    polar surface area110.21ChemAxon
    rotatable bond count15ChemAxon
    refractivity149.12ChemAxon
    polarizability61.17ChemAxon
    number of rings3ChemAxon
    bioavailability0ChemAxon
    rule of fiveNoChemAxon
    Ghose filterNoChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleYesChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    Sandra Gallego Pato, Antonio Palomo Coll, Francisco Palomo Nicolau, “Preparation of crystalline polymorphs of fosinopril sodium.” U.S. Patent US20050010054, issued January 13, 2005.

    US20050010054
    General Reference
    1. David D, Jallad N, Germino FW, Willett MS, de Silva J, Weidner SM, Mills DJ: A Comparison of the Cough Profile of Fosinopril and Enalapril in Hypertensive Patients with a History of ACE Inhibitor-Associated Cough. Am J Ther. 1995 Oct;2(10):806-813. Pubmed
    2. Sharma S, Deitchman D, Eni JS, Gelperin K, Ilgenfritz JP, Blumenthal M: The hemodynamic effects of long-term ACE inhibition with fosinopril in patients with heart failure. Fosinopril Hemodynamics Study Group. Am J Ther. 1999 Jul;6(4):181-9. Pubmed
    External Links
    ResourceLink
    KEGG DrugD00622
    KEGG CompoundC07016
    PubChem Compound55891
    PubChem Substance46506495
    ChemSpider50469
    ChEBI5163
    ChEMBLCHEMBL1201310
    Therapeutic Targets DatabaseDAP000582
    PharmGKBPA449710
    Drug Product Database2262428
    RxListhttp://www.rxlist.com/cgi/generic/fosinop.htm
    Drugs.comhttp://www.drugs.com/cdi/fosinopril.html
    PDRhealthhttp://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=Mon1274.html&contentName=Monopril&contentId=
    WikipediaFosinopril
    ATC CodesC09AA09
    AHFS Codes
    • 24:32.04
    PDB Entries
    FDA labelshow(206 KB)
    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
    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
    Food Interactions
    • Do not take calcium, aluminum, magnesium or iron supplements, or antacids within 2 hours of taking this medication.
    • Fosinopril may decrease the excretion of potassium. Salt substitutes containing potassium may increase the risk of hyperkalemia.
    • Herbs that may attenuate the antihypertensive effect of fosinopril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
    • High salt intake may attenuate the antihypertensive effect of fosinopril.
    • 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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
    2. Ondetti MA: Structural relationships of angiotensin converting-enzyme inhibitors to pharmacologic activity. Circulation. 1988 Jun;77(6 Pt 2):I74-8. Pubmed
    3. Piepho RW: Overview of the angiotensin-converting-enzyme inhibitors. Am J Health Syst Pharm. 2000 Oct 1;57 Suppl 1:S3-7. Pubmed
    4. Sharma S, Deitchman D, Eni JS, Gelperin K, Ilgenfritz JP, Blumenthal M: The hemodynamic effects of long-term ACE inhibition with fosinopril in patients with heart failure. Fosinopril Hemodynamics Study Group. Am J Ther. 1999 Jul;6(4):181-9. 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 17:10