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Identification
Name Captopril
Accession Number DB01197 (APRD00164)
Type small molecule
Groups approved
Description

Captopril is a potent, competitive inhibitor of angiotensin-converting enzyme (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). Captopril may be used in the treatment of hypertension.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Captoprilum [INN-Latin]
  • Captopryl
  • L-Captopril
Brand names
  • Acepress (Bernofarm (Indonesia), BMS (Italy))
  • Acepril (BMS (United Kingdom))
  • Alopresin
  • Apopril
  • Capoten (Bristol-Myers Squibb, Par)
  • Captolane (Sanofi-Aventis (France))
  • Captoril (Novopharm (Canada))
  • Cesplon (Esteve (Spain))
  • Dilabar (Qualigen (Spain))
  • Garranil (discontinued) (Aristegui (Spain))
  • Hipertil (Normal (Portugal))
  • Hypertil (Normal (Portugal))
  • Lopirin (BMS (Germany,Switzerland))
  • Lopril (Orion (Finland), BMS (France))
  • Tenosbon
  • Tensoprel (Rubio (Spain))
Brand name mixtures
  • Acediur (captopril + hydrochlorothiazide)
  • Aceplus (captopril + hydrochlorothiazide)
  • Capozide (captopril + hydrochlorothiazide)
Categories
  • Antihypertensive Agents
  • Angiotensin-converting Enzyme Inhibitors
CAS number 62571-86-2
Weight Average: 217.285
Monoisotopic: 217.077264041
Chemical Formula C9H15NO3S
InChI Key InChIKey=FAKRSMQSSFJEIM-RQJHMYQMSA-N
InChI
InChI=1S/C9H15NO3S/c1-6(5-14)8(11)10-4-2-3-7(10)9(12)13/h6-7,14H,2-5H2,1H3,(H,12,13)/t6-,7+/m1/s1
Plain Text
IUPAC Name
(2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid
SMILES
C[C@H](CS)C(=O)N1CCC[C@H]1C(O)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For the treatment of essential or renovascular hypertension (usually administered with other drugs, particularly thiazide diuretics). May be used to treat congestive heart failure in combination with other drugs (e.g. cardiac glycosides, diuretics, β-adrenergic blockers). May improve survival in patients with left ventricular dysfunction following myocardial infarction. May be used to treat nephropathy, including diabetic nephropathy.
Pharmacodynamics Captopril, an ACE inhibitor, antagonizes 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 its effects 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. Captopril, one of the few ACE inhibitors that is not a prodrug, 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. Captopril 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. Captopril’s affinity for ACE is approximately 30,000 times greater than that of ATI.
Absorption 60-75% in fasting individuals; food decreases absorption by 25-40% (some evidence indicates that this is not clinically significant)
Volume of distribution Not Available
Protein binding 25-30% bound to plasma proteins, primarily albumin
Metabolism

Hepatic. Major metabolites are captopril-cysteine disulfide and the disulfide dimer of captopril. Metabolites may undergo reversible interconversion.

Route of elimination Not Available
Half life 2 hours
Clearance Not Available
Toxicity Symptoms of overdose include emesis and decreased blood pressure. Side effects include dose-dependent rash (usually maculopapular), taste alterations, hypotension, gastric irritation, cough, and angioedema.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00146 Captopril Pathway SMP00146
Pharmacoeconomics
Manufacturers
  • Par pharmaceutical inc
  • Apotex inc
  • Apothecon inc div bristol myers squibb
  • Clonmel healthcare ltd
  • Egis pharmaceuticals ltd
  • Endo laboratories inc div dupont merck pharmaceutical co
  • Huahai us inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mylan laboratories inc
  • Purepac pharmaceutical co
  • Sandoz inc
  • Stason industrial corp
  • Teva pharmaceuticals usa inc
  • Teva pharmaceuticals usa
  • Watson laboratories inc
  • West ward pharmaceutical corp
  • Wockhardt americas inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral 100 mg
Tablet Oral 12.5 mg
Tablet Oral 25 mg
Tablet Oral 50 mg
Prices
Unit description Cost Unit
Captopril powder 22.03 USD g
Capoten 100 mg tablet 4.53 USD tablet
Capoten 12.5 mg tablet 1.8 USD tablet
Captopril 100 mg tablet 1.53 USD tablet
Captopril 50 mg tablet 1.14 USD tablet
Capoten 25 mg tablet 1.13 USD tablet
Capoten 50 mg tablet 1.13 USD tablet
Apo-Capto 100 mg Tablet 1.09 USD tablet
Mylan-Captopril 100 mg Tablet 1.09 USD tablet
Novo-Captoril 100 mg Tablet 1.09 USD tablet
Nu-Capto 100 mg Tablet 1.09 USD tablet
Captopril 25 mg tablet 0.67 USD tablet
Captopril 12.5 mg tablet 0.62 USD tablet
Apo-Capto 50 mg Tablet 0.59 USD tablet
Mylan-Captopril 50 mg Tablet 0.59 USD tablet
Novo-Captoril 50 mg Tablet 0.59 USD tablet
Nu-Capto 50 mg Tablet 0.59 USD tablet
Apo-Capto 25 mg Tablet 0.31 USD tablet
Mylan-Captopril 25 mg Tablet 0.31 USD tablet
Novo-Captoril 25 mg Tablet 0.31 USD tablet
Nu-Capto 25 mg Tablet 0.31 USD tablet
Apo-Capto 12.5 mg Tablet 0.22 USD tablet
Mylan-Captopril 12.5 mg Tablet 0.22 USD tablet
Novo-Captoril 12.5 mg Tablet 0.22 USD tablet
Nu-Capto 12.5 mg Tablet 0.22 USD tablet
Patents
Country Patent Number Approved Expires
United States 5238924 1993-08-24 2010-08-24
Properties
State solid
Melting point 106oC
Experimental Properties
Property Value Source
water solubility Freely soluble PhysProp
logP 0.6 PhysProp
Predicted Properties
Property Value Source
water solubility 4.52e+00 g/l ALOGPS
logP 1.02 ALOGPS
logP 0.73 ChemAxon Molconvert
logS -1.68 ALOGPS
pKa 10.10 ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 57.61 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 54.63 ChemAxon Molconvert
polarizability 21.79 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Atkinson AB, Robertson JI: Captopril in the treatment of clinical hypertension and cardiac failure. Lancet. 1979 Oct 20;2(8147):836-9. Pubmed
  2. Patchett AA, Harris E, Tristram EW, Wyvratt MJ, Wu MT, Taub D, Peterson ER, Ikeler TJ, ten Broeke J, Payne LG, Ondeyka DL, Thorsett ED, Greenlee WJ, Lohr NS, Hoffsommer RD, Joshua H, Ruyle WV, Rothrock JW, Aster SD, Maycock AL, Robinson FM, Hirschmann R, Sweet CS, Ulm EH, Gross DM, Vassil TC, Stone CA: A new class of angiotensin-converting enzyme inhibitors. Nature. 1980 Nov 20;288(5788):280-3. Pubmed
  3. Smith CG, Vane JR: The discovery of captopril. FASEB J. 2003 May;17(8):788-9. Pubmed
External Links
Resource Link
KEGG Drug D00251 Link_out
PubChem Compound 44093 Link_out
PubChem Substance 46506879 Link_out
ChemSpider 40130 Link_out
BindingDB 21642 Link_out
ChEBI 3380 Link_out
ChEMBL 3380 Link_out
Therapeutic Targets Database DAP000589 Link_out
PharmGKB PA448780 Link_out
Drug Product Database 2242791 Link_out
RxList http://www.rxlist.com/cgi/generic/captop.htm Link_out
Drugs.com http://www.drugs.com/captopril.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/cap1064.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Captopril Link_out
ATC Codes
  • C09AA01
AHFS Codes
  • 24:32.04
PDB Entries
FDA label Not Available
MSDS show (37.6 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Captopril decreases the excretion of potassium. Salt substitutes containing potassium increase the risk of hyperkalemia.
  • Food decreases absorption by 25 - 40%. Clinical significance is debatable.
  • Herbs that may attenuate the antihypertensive effect of captopril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
  • High salt intake may attenuate the antihypertensive effect of captopril.
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. Andujar-Sanchez M, Jara-Perez V, Camara-Artigas A: Thermodynamic determination of the binding constants of angiotensin-converting enzyme inhibitors by a displacement method. FEBS Lett. 2007 Jul 24;581(18):3449-54. Epub 2007 Jun 27. Pubmed
  2. Dalkas GA, Marchand D, Galleyrand JC, Martinez J, Spyroulias GA, Cordopatis P, Cavelier F: Study of a lipophilic captopril analogue binding to angiotensin I converting enzyme. J Pept Sci. 2010 Feb;16(2):91-7. Pubmed
  3. Natesh R, Schwager SL, Evans HR, Sturrock ED, Acharya KR: Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. Biochemistry. 2004 Jul 13;43(27):8718-24. Pubmed
  4. Piepho RW: Overview of the angiotensin-converting-enzyme inhibitors. Am J Health Syst Pharm. 2000 Oct 1;57 Suppl 1:S3-7. Pubmed
  5. 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
  6. Tzakos AG, Naqvi N, Comporozos K, Pierattelli R, Theodorou V, Husain A, Gerothanassis IP: The molecular basis for the selection of captopril cis and trans conformations by angiotensin I converting enzyme. Bioorg Med Chem Lett. 2006 Oct 1;16(19):5084-7. Epub 2006 Aug 2. Pubmed
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. 72 kDa type IV collagenase

Pharmacological action: unknown
Actions: inhibitor

In addition to gelatin and collagens, it cleaves KiSS1 at a Gly-|-Leu bond

Organism class: human
UniProt ID: P08253 Link_out
Gene: MMP2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Brower GL, Levick SP, Janicki JS: Inhibition of matrix metalloproteinase activity by ACE inhibitors prevents left ventricular remodeling in a rat model of heart failure. Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H3057-64. Epub 2007 Feb 16. Pubmed
  2. Okada M, Kikuzuki R, Harada T, Hori Y, Yamawaki H, Hara Y: Captopril attenuates matrix metalloproteinase-2 and -9 in monocrotaline-induced right ventricular hypertrophy in rats. J Pharmacol Sci. 2008 Dec;108(4):487-94. Epub 2008 Dec 5. Pubmed
  3. Prontera C, Mariani B, Rossi C, Poggi A, Rotilio D: Inhibition of gelatinase A (MMP-2) by batimastat and captopril reduces tumor growth and lung metastases in mice bearing Lewis lung carcinoma. Int J Cancer. 1999 May 31;81(5):761-6. Pubmed
  4. Reinhardt D, Sigusch HH, Hensse J, Tyagi SC, Korfer R, Figulla HR: Cardiac remodelling in end stage heart failure: upregulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP. Heart. 2002 Nov;88(5):525-30. Pubmed
  5. Williams RN, Parsons SL, Morris TM, Rowlands BJ, Watson SA: Inhibition of matrix metalloproteinase activity and growth of gastric adenocarcinoma cells by an angiotensin converting enzyme inhibitor in in vitro and murine models. Eur J Surg Oncol. 2005 Nov;31(9):1042-50. Epub 2005 Jul 1. Pubmed
  6. Yamamoto D, Takai S, Hirahara I, Kusano E: Captopril directly inhibits matrix metalloproteinase-2 activity in continuous ambulatory peritoneal dialysis therapy. Clin Chim Acta. 2010 May 2;411(9-10):762-4. Epub 2010 Feb 22. Pubmed

3. Matrix metalloproteinase-9

Pharmacological action: unknown
Actions: inhibitor

May play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration. Could play a role in bone osteoclastic resorption. Cleaves KiSS1 at a Gly-|-Leu bond

Organism class: human
UniProt ID: P14780 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA

References:
  1. Okada M, Kikuzuki R, Harada T, Hori Y, Yamawaki H, Hara Y: Captopril attenuates matrix metalloproteinase-2 and -9 in monocrotaline-induced right ventricular hypertrophy in rats. J Pharmacol Sci. 2008 Dec;108(4):487-94. Epub 2008 Dec 5. Pubmed
  2. Reinhardt D, Sigusch HH, Hensse J, Tyagi SC, Korfer R, Figulla HR: Cardiac remodelling in end stage heart failure: upregulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP. Heart. 2002 Nov;88(5):525-30. Pubmed
  3. Williams RN, Parsons SL, Morris TM, Rowlands BJ, Watson SA: Inhibition of matrix metalloproteinase activity and growth of gastric adenocarcinoma cells by an angiotensin converting enzyme inhibitor in in vitro and murine models. Eur J Surg Oncol. 2005 Nov;31(9):1042-50. Epub 2005 Jul 1. Pubmed
  4. Yamamoto D, Takai S, Miyazaki M: Inhibitory profiles of captopril on matrix metalloproteinase-9 activity. Eur J Pharmacol. 2008 Jul 7;588(2-3):277-9. Epub 2008 May 22. Pubmed
Enzymes

1. Cytochrome P450 2D6

Actions: substrate

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 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: inhibitor

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. Watanabe K, Sawano T, Terada K, Endo T, Sakata M, Sato J: Studies on intestinal absorption of sulpiride (1): carrier-mediated uptake of sulpiride in the human intestinal cell line Caco-2. Biol Pharm Bull. 2002 Jul;25(7):885-90. Pubmed
  2. Temple CS, Boyd CA: Proton-coupled oligopeptide transport by rat renal cortical brush border membrane vesicles: a functional analysis using ACE inhibitors to determine the isoform of the transporter. Biochim Biophys Acta. 1998 Aug 14;1373(1):277-81. Pubmed

3. Solute carrier family 22 member 6

Actions: inhibitor
UniProt ID: Q4U2R8 Link_out
Gene: hROAT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kuze K, Graves P, Leahy A, Wilson P, Stuhlmann H, You G: Heterologous expression and functional characterization of a mouse renal organic anion transporter in mammalian cells. J Biol Chem. 1999 Jan 15;274(3):1519-24. Pubmed
Carriers

1. Serum albumin

Actions: other/unknown

Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood

UniProt ID: P02768 Link_out
Gene: ALB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Keire DA, Mariappan SV, Peng J, Rabenstein DL: Nuclear magnetic resonance studies of the binding of captopril and penicillamine by serum albumin. Biochem Pharmacol. 1993 Sep 14;46(6):1059-69. Pubmed
  2. Lin SY, Wei YS, Li MJ, Wang SL: Effect of ethanol or/and captopril on the secondary structure of human serum albumin before and after protein binding. Eur J Pharm Biopharm. 2004 May;57(3):457-64. Pubmed
  3. Mariee AD, Al-Shabanah O: Protective ability and binding affinity of captopril towards serum albumin in an in vitro glycation model of diabetes mellitus. J Pharm Biomed Anal. 2006 May 3;41(2):571-5. Epub 2006 Feb 15. Pubmed
  4. Narazaki R, Harada K, Sugii A, Otagiri M: Kinetic analysis of the covalent binding of captopril to human serum albumin. J Pharm Sci. 1997 Feb;86(2):215-9. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:46

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.