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Identification
Name Fosinopril
Accession Number DB00492 (APRD00526)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Fosinopril Sodium
Salts Not Available
Brand names
Name Company
Acecor SPA (Czech Republic)
Monopril Bristol-Myers Squibb
Staril BMS (United Kingdom)
Brand mixtures
Brand Name Ingredients
Monopril-HCT fosinopril sodium + hydrochlorothiazide
Categories
  • Antihypertensive Agents
  • Angiotensin-converting Enzyme Inhibitors
CAS number 98048-97-6
Weight Average: 563.6625
Monoisotopic: 563.301189343
Chemical Formula C30H46NO7P
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzene and Derivatives
  • Amino Acids
Substructures
  • Carboxylic Acids and Derivatives
  • Hydroxy Compounds
  • Acetates
  • Amino Ketones
  • Pyrrolidines
  • Ethers
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Amino Acids
Pharmacology
Indication For 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.
Pharmacodynamics Following 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 action There 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.
Absorption Average 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 distribution Not Available
Protein binding Fosinoprilat 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.
Route of elimination After 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 life 12 hours
Clearance
  • 26 – 39 mL/min [healthy]
Toxicity Human 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
Pathway Name SMPDB ID
Smp00149 Fosinopril Pathway SMP00149
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
Form Route Strength
Tablet Oral 10 mg
Tablet Oral 20 mg
Tablet Oral 40 mg
Prices
Unit description Cost Unit
Monopril HCT 10-12.5 mg tablet 1.71 USD tablet
Monopril 10 mg tablet 1.68 USD tablet
Monopril 40 mg tablet 1.67 USD tablet
Monopril 20 mg tablet 1.62 USD tablet
Fosinopril Sodium-HCTZ 10-12.5 mg tablet 1.61 USD tablet
Fosinopril Sodium-HCTZ 20-12.5 mg tablet 1.61 USD tablet
Fosinopril sodium 20 mg tablet 1.25 USD tablet
Fosinopril sodium 40 mg tablet 1.25 USD tablet
Fosinopril sodium 10 mg tablet 1.21 USD tablet
Monopril 20 mg Tablet 1.1 USD tablet
Monopril 10 mg Tablet 0.91 USD tablet
Apo-Fosinopril 20 mg Tablet 0.61 USD tablet
Fosinopril 20 mg Tablet 0.61 USD tablet
Jamp-Fosinopril 20 mg Tablet 0.61 USD tablet
Mylan-Fosinopril 20 mg Tablet 0.61 USD tablet
Novo-Fosinopril 20 mg Tablet 0.61 USD tablet
Ran-Fosinopril 20 mg Tablet 0.61 USD tablet
Apo-Fosinopril 10 mg Tablet 0.51 USD tablet
Fosinopril 10 mg Tablet 0.51 USD tablet
Jamp-Fosinopril 10 mg Tablet 0.51 USD tablet
Mylan-Fosinopril 10 mg Tablet 0.51 USD tablet
Novo-Fosinopril 10 mg Tablet 0.51 USD tablet
Ran-Fosinopril 10 mg Tablet 0.51 USD tablet
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Patents
Country Patent Number Approved Expires (estimated)
United States 5006344 1993-01-10 2010-01-10
Properties
State solid
Experimental Properties
Property Value Source
melting point 149-153 °C Not Available
water solubility Insoluble Not Available
logP 6.3 Not Available
Predicted Properties
Property Value Source
water solubility 1.01e-03 g/l ALOGPS
logP 4.71 ALOGPS
logP 5.49 ChemAxon
logS -5.8 ALOGPS
pKa (strongest acidic) 3.87 ChemAxon
pKa (strongest basic) -4.4 ChemAxon
physiological charge -1 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 110.21 ChemAxon
rotatable bond count 15 ChemAxon
refractivity 149.12 ChemAxon
polarizability 61.17 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00622 Link_out
KEGG Compound C07016 Link_out
PubChem Compound 55891 Link_out
PubChem Substance 46506495 Link_out
ChemSpider 50469 Link_out
ChEBI 5163 Link_out
ChEMBL 5163 Link_out
Therapeutic Targets Database DAP000582 Link_out
PharmGKB PA449710 Link_out
Drug Product Database 2262428 Link_out
RxList http://www.rxlist.com/cgi/generic/fosinop.htm Link_out
Drugs.com http://www.drugs.com/cdi/fosinopril.html Link_out
PDRhealth http://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=Mon1274.html&contentName=Monopril&contentId= Link_out
Wikipedia http://en.wikipedia.org/wiki/Fosinopril Link_out
ATC Codes
  • C09AA09
AHFS Codes
  • 24:32.04
PDB Entries
FDA label show (206 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Amiloride Increased risk of hyperkalemia
Azilsartan medoxomil Pharmacodynamic synergism: dual blockade of renin-angiotensin system. Increases risks of hypotension, hyperkalemia, renal impairment.
Drospirenone Increased risk of hyperkalemia
Icatibant Icatibant may attenuate the antihypertensive effect of ACE inhibitors by pharmacodynamic antagonism. Monitor concomitant therapy closely.
Lithium The ACE inhibitor increases serum levels of lithium
Potassium Increased risk of hyperkalemia
Spironolactone Increased risk of hyperkalemia
Tizanidine Tizanidine increases the risk of hypotension with the ACE inhibitor
Tobramycin Increased risk of nephrotoxicity
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Triamterene Increased 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.
Targets

1. Angiotensin-converting enzyme

Pharmacological action: yes
Actions: inhibitor

Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator

Organism class: human
UniProt ID: P12821 Link_out
Gene: ACE Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Transporters

1. Oligopeptide transporter, small intestine isoform

Actions: substrate

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products

UniProt ID: P46059 Link_out
Gene: SLC15A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Oligopeptide transporter, kidney isoform

Actions: substrate

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides

UniProt ID: Q16348 Link_out
Gene: SLC15A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 February 08, 2013 16:19