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Identification
Name Perindopril
Accession Number DB00790 (APRD01178)
Type small molecule
Groups approved
Description

Perindopril erbumine is a nonsulfhydryl prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is rapidly metabolized in the liver to perindoprilat, its active metabolite, following oral administration. Perindoprilat is a potent, 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). Perindopril may be used to treat mild to moderate essential hypertension, mild to moderate congestive heart failure, and to reduce the cardiovascular risk of individuals with hypertension or post-myocardial infarction and stable coronary disease.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Perindopril Erbumine
Brand names
  • Aceon (Solvay)
  • Coversyl (Servier)
Brand name mixtures
  • Coversyl Plus (perindopril erbumine + indapamide)
  • Preterax (perindopril erbumine + indapamide)
Categories
  • Antihypertensive Agents
  • Angiotensin-converting Enzyme Inhibitors
CAS number 107133-36-8
Weight Average: 368.4678
Monoisotopic: 368.231122144
Chemical Formula C19H32N2O5
InChI Key InChIKey=IPVQLZZIHOAWMC-QXKUPLGCSA-N
InChI
InChI=1S/C19H32N2O5/c1-4-8-14(19(25)26-5-2)20-12(3)17(22)21-15-10-7-6-9-13(15)11-16(21)18(23)24/h12-16,20H,4-11H2,1-3H3,(H,23,24)/t12-,13-,14-,15-,16-/m0/s1
Plain Text
IUPAC Name
(2S,3aS,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxopentan-2-yl]amino}propanoyl]-octahydro-1H-indole-2-carboxylic acid
SMILES
[H][C@]12C[C@H](N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@@]1([H])CCCC2)C(O)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Carboxylic Acids and Derivatives
  • Polypeptides
Substructures
  • Carboxylic Acids and Derivatives
  • Hydroxy Compounds
  • Acetates
  • Aliphatic and Aryl Amines
  • Amino Ketones
  • Pyrrolidines
  • Ethers
  • Polypeptides
  • Heterocyclic compounds
  • Carboxamides and Derivatives
  • Amino Acids
Pharmacology
Indication For the treatment of mild to moderate essential hypertension, mild to moderate congestive heart failure, and to reduce the cardiovascular risk of individuals with hypertension or post-myocardial infarction and stable coronary disease.
Pharmacodynamics Perindopril is a nonsulfhydryl prodrug that is metabolized via first pass effect (62%) and systemic hydrolysis (38%) to perindoprilat, its active metabolite, following oral administration. Perindoprilat 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 perindoprilat 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. Perindoprilat, the active metabolite of perindopril, 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. Perindopril 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 Rapidly absorbed with peak plasma concentrations occurring approximately 1 hour after oral administration. Bioavailability is 65-75%. Following absorption, perindopril is hydrolyzed to perindoprilat, which has an average bioavailability of 20%. The rate and extent of absorption is unaffected by food. However, food decreases the extent of biotransformation to peridoprilat and reduces its bioavailability by 35%.
Volume of distribution Not Available
Protein binding Perindoprilat, 10-20% bound to plasma proteins
Metabolism

Extensively metabolized, with only 4-12% of the dose recovered in urine following oral administration. Six metabolites have been identified: perindoprilat, perindopril glucuronide, perindoprilat glucuronide, a perindopril lactam, and two perindoprilat lactams. Only perindoprilat is pharmacologically active. Peridoprilat and perindoprilat glucuronide are the two main circulating metabolites.

Route of elimination Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine.
Half life Perindopril, 1.2 hours; Peridoprilat, 30-120 hours. The long half life of peridoprilat is due to its slow dissociation from ACE binding sites.
Clearance
  • 219 – 362 mL/min [oral administration]
Toxicity The most likely symptom of overdose is severe hypotension. The most common adverse effects observed in controlled clinical trials include cough, digestive symptoms, fatigue, headache, and dizziness.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00152 Perindopril Pathway SMP00152
Pharmacoeconomics
Manufacturers
  • Abbott products inc
  • Aurobindo pharma ltd
  • Ivax pharmaceuticals inc
  • Lupin ltd
  • Roxane laboratories inc
Packagers
Dosage forms
Form Route Strength
Tablet, film coated Oral 2 mg
Tablet, film coated Oral 4 mg
Tablet, film coated Oral 8 mg
Prices
Unit description Cost Unit
Aceon 8 mg tablet 3.14 USD tablet
Perindopril erbumine 8 mg tablet 2.8 USD tablet
Aceon 4 mg tablet 2.58 USD tablet
Perindopril erbumine 4 mg tablet 2.3 USD tablet
Aceon 2 mg tablet 2.22 USD tablet
Perindopril erbumine 2 mg tablet 1.98 USD tablet
Coversyl 8 mg Tablet 1.23 USD tablet
Coversyl 4 mg Tablet 0.88 USD tablet
Coversyl 2 mg Tablet 0.7 USD tablet
Patents
Country Patent Number Approved Expires
United States 5162362 1992-11-10 2009-11-10
Canada 2473205 2010-05-18 2023-01-22
Canada 1341196 2001-03-06 2018-03-06
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
logP 2.6 PhysProp
Predicted Properties
Property Value Source
water solubility 1.22e+00 g/l ALOGPS
logP 0.56 ALOGPS
logP 0.59 ChemAxon Molconvert
logS -2.48 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 95.94 ChemAxon Molconvert
rotatable bond count 9 ChemAxon Molconvert
refractivity 95.69 ChemAxon Molconvert
polarizability 40.00 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Hurst M, Jarvis B: Perindopril: an updated review of its use in hypertension. Drugs. 2001;61(6):867-96. Pubmed
  2. Jastrzebskal M, Widecka K, Naruszewicz M, Ciechanowicz A, Janczak-Bazan A, Foltynska A, Goracy I, Chetstowski K, Wesotowska T: Effects of perindopril treatment on hemostatic function in patients with essential hypertension in relation to angiotensin converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms. Nutr Metab Cardiovasc Dis. 2004 Oct;14(5):259-69. Pubmed
  3. Parker E, Aarons L, Rowland M, Resplandy G: The pharmacokinetics of perindoprilat in normal volunteers and patients: influence of age and disease state. Eur J Pharm Sci. 2005 Sep;26(1):104-13. Pubmed
  4. Simpson D, Noble S, Goa KL: Perindopril: in congestive heart failure. Drugs. 2002;62(9):1367-77; discussion 1378-9. Pubmed
  5. Yasumatsu R, Nakashima T, Masuda M, Ito A, Kuratomi Y, Nakagawa T, Komune S: Effects of the angiotensin-I converting enzyme inhibitor perindopril on tumor growth and angiogenesis in head and neck squamous cell carcinoma cells. J Cancer Res Clin Oncol. 2004 Oct;130(10):567-73. Epub 2004 Jul 27. Pubmed
  6. Yoshiji H, Kuriyama S, Kawata M, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Fukui H: The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor. Clin Cancer Res. 2001 Apr;7(4):1073-8. Pubmed
External Links
Resource Link
KEGG Drug D00624 Link_out
KEGG Compound C07707 Link_out
PubChem Compound 107807 Link_out
PubChem Substance 46508767 Link_out
ChemSpider 96956 Link_out
ChEBI 8025 Link_out
ChEMBL 8025 Link_out
Therapeutic Targets Database DNC001114 Link_out
PharmGKB PA450878 Link_out
Drug Product Database 2246624 Link_out
RxList http://www.rxlist.com/cgi/generic/aceon.htm Link_out
Drugs.com http://www.drugs.com/cdi/perindopril.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ace1543.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Perindopril Link_out
ATC Codes
  • C09AA04
AHFS Codes
  • 24:32.04
PDB Entries Not Available
FDA label show (149.3 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Herbs that may attenuate the antihypertensive effect of perindopril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
  • High salt intake may attenuate the antihypertensive effect of perindopril.
  • Perindopril may decrease the excretion of potassium. Salt substitutes containing potassium may increase the risk of hyperkalemia.
  • 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. Alfakih K, Hall AS: Perindopril. Expert Opin Pharmacother. 2006 Jan;7(1):63-71. Pubmed
  2. Brugts JJ, Ferrari R, Simoons ML: Angiotensin-converting enzyme inhibition by perindopril in the treatment of cardiovascular disease. Expert Rev Cardiovasc Ther. 2009 Apr;7(4):345-60. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. 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
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. 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

3. 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 November 10, 2010 13:42

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.