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Captopril

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GENERAL FEATURES

Name: Captopril
Generic Names: SQ 14225[1],[2],[45]
D-3-mercapto-2-methyl-propanoyl-L-proline[3], [4],[2]
1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline[5],[6],[7]
( [2S]-1-[3-mercapto-2-methyl-propionyl]-L-proline)[6]
Trade Names: Capoten®[45]
IUPAC name:
(2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]Pyrrolidine-2-carboxylic Acid[8]
Molecular Weight:
Structure:
[5], [9], [6], [10], [3], [11], [12], [13], [4], [2],[40],[41],[42],[43],[45]
Functional Group/
chemical
constitution:
Captopril has sulfhydryl group in its structure[11],[4]
and it is a derivative of amino-acid proline[14]
Captopril is a dipeptide analogue containing L-proline and a D-3-mercapto-methylpropanoyl group[15]
Sulfhydryl group(-SH) of captopril undergoes oxidative dimerization or conjugation[13]
Thiol group[16]
Proline ring in captopril exhibits envelope conformation [8].
Intermolecular O-H...O and relatively weak C-H...O interactions , also S-H...O and C-H...S contacts are found to be present
[8]
Chemical Nature: sulfhydryl-containing analogue of proline[17] The sulfhydryl group of captopril is very reactive[5], [11]
Captopril has affinity for divalent cations[11]
trans form was the active form of captopril[13]
Captopril has reducing properties because of which it can reduce metal ions enabling their participation in the Fenton reaction[6]
an optically active molecule[2]
Captopril was found to be quite stable in aqueous solution (at acidic or neutral pH) in the absence of metal ions[2]
Actions
& Indications:
Pharmcological Action-
Hypotensive effect[18]
Acts as a prooxidant(not as a antioxidant) when interacts with iron and copper[19]
Antioxidant[20]
free-radical scavenging action[21],[16]
inhibitor of the conversion enzyme[22]
Prooxidant at high concentration[6]
Antioxidant at low concentration[6]
angiotensin-converting enzyme inhibitoer, ACEI[23], in rabbits in vivo(1 mg/kg, 1 mg/kg, IV)[42]
Therapeutic benefits/Indications:
Captopril is indicated in heart failure, other vascular diseases and hypertension[14], FDA approvd drug in treatment of hypertension in human[24], also in long-term treatment of hypertensive patients[1]
Captopril is indicated in patients after myocardial infarction, patients with dilated cardiomyopathy, patients with chronic kidney disease[25]
Captopril(37.5-100mg daily) protects kidney function and against albuminaria and is employed in treatment of hypertension in patients with insulin dependent diabetics with nephropathy[26]
Captopril has been shown clinically to reduce proteinuria, urinary cystine excretion by forming captopril-cysteine disulfide and stabilize renal function in two patients with cystinuria[27]
Captopril has an efficacy in the treatment of arterial hypertension[18]
and congestive cardiac insufficiency[22]
Preclinical study-
Pretreatment of dogs with captopril (5mg/kg, IV) resulted in a 40 to 60% return to active shortening within 60 min of reperfusion[28]
Captopril reduced density of magnesium-induced myocardial lesions, degree of inflammatory infiltration around blood vessels in Golden Syrian male hamsters[29]
Captopril attenuated endothelium-dependent contractions induced by pyrogallol(a potent generator of O2-) in rabbit aortic rings[30]
Captopril(up to 50 mg twice daily) inhibited angiogensis in a patient with Kaposi's sarcoma[31]
Captopril(5mg/kg, IP)could significantly reduce serum TNF-alpha level, elevate PaO2 and reduce PaCO2 in rats with ALI(constructed by intratracheal injection of diluted HCl)[32]
Captopril oral administration (25-50mg/kg/day) showed a significant decrease in aortic atherosclerosis in normotensive Watanabe heritable hyperlipidemic rabbits[33]
Captopril suppressed IL-12 production by human peripheral blood mononuclear cells stimulated with bacterial lipopolysaccharide or Staphylococcus aureus Cowan[34]
Captopril in vivo prevented the induction of neovascularization in rats and also retarded growth of sygeneic rat fibrosarcoma SC injected in rat[35]
Captopril has anti-mitotic activity[36]
Captopril(25-50mg/kg, orally) exhibited a potent antiatherosclerotic action in the Watanabe heritable hyperlipidemic rabbit.[33]
Oral administration of captopril was found to be effective in long-term treatment of hypertensive patients[1]
Captopril is suspected to be effective in mitigating lung injury from nuclear accidents or terrorist event[37]
captopril is shown to protection against complement-mediated myocardial injury in isolated perfused rabbit heart, hence suggested to ptotect during myocardial ischemia and reperfusion[23]
Captopril (100 mg/kg orally) significantly inhibited pressor responses to sympathetic nerve stimulation and norepinephrine in spontaneouslyhypertensive rats[39]
Long-term use of ACE inhibitors - captopril is suggested protect against cancer.[44]
Notes: Sulfhydryl group can react with blood components or be oxidized to captopril disulfide and mixed disulfides[5]
Captopril, at a concentration of 1mg/ml, made with distilled water stored in PVC container and protected from light was found to be stable for 30 days at 4oC[9]
Captopril can reduce metal ions enabling their participation in the Fenton reaction[6]
Captopril protected erythrocytes from hemolysis caused by 2,2'-azobis(2-amidinopropane)(AAPH) and hypochlorite, also protected erythrocyte membrane from lipid peroxidation caused by tert-butyl hydroperoxide(tBOOH), also erythrocyte membrane ATPase and hemoglobin from oxidation by AAPH and tBOOH[6]
Captopril after a certain threshold concentration found to inhibit plasmin and angiostatin formation hence one should be cautioned not to administer an excess of captopril in an in vivo experiments as it may become counterproductive[38]
A limitation of all the studies involving ACE inhibitor Captopril against lung injury is that a single time point (often at the peak of pneumonitis) was often used for analysis, hence it is not clear whether ACE inhibition decreases the magnitude of the pneumonitis or merely delays it[37]
Due to the relatively short elimination half-life of captopril the use of disulfide analogs of captopril have been considered as possible prodrugs to prolong the action of captopril.[41]
Derivatives
/analogues:
Analogue 'Zofenopril(SQ 26, 703)' and Stereoisomer of captopril 'SQ 14, 534' could inhibit superoxide-mediated autoxidation of epinephrine.[28]
REFERENCES
1. Brunner HR et al, Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients. Ann Intern Med. 1979;90(1):19-23.
http://dx.doi.org/10.7326/0003-4819-90-1-19
2. Migdalof BH et al, Captopril: pharmacology, metabolism and disposition. Drug Metab Rev. 1984;15(4):841-69.
http://dx.doi.org/10.3109/03602538409041080
3. Kriplani KJ et al, Disposition of captopril in normal subjects. Clin Pharmacol Ther. 1980;27(5):636-41.
http://dx.doi.org/10.1038/clpt.1980.90
4. Duchin KL et al, Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases. Clin Pharmacokinet. 1988 ;14(4):241-59.
http://dx.doi.org/10.2165/00003088-198814040-00002
5. Ivashkiv E, Spectrofluorometric determination of captopril plus captopril disulfide metabolites in plasma. J Pharm Sci. 1984 ;73(10):1427-30.
http://dx.doi.org/10.1002/jps.2600731026
6. Bartosz M, Kedziora J, Bartosz G, Antioxidant and prooxidant properties of captopril and enalapril. Free Radic Biol Med. 1997;23(5):729-35.
http://dx.doi.org/10.1016/S0891-5849(97)00014-2
7. Bathala MS et al, Quantitative determination of captopril in blood and captopril and its disulfide metabolites in plasma by gas chromatography. J Pharm Sci. 1984;73(3):340-4.
http://dx.doi.org/10.1002/jps.2600730313
8. Bojarska J et al, Captopril and its dimer captopril disulfide: comparative structural and conformational studies. Acta Crystallogr C Struct Chem. 2015;71(Pt 3):199-203.
http://dx.doi.org/10.1107/S2053229615002582
9. Escribano García MJ, Torrado Durán S, Torrado Durán JJ, Stability study of an aqueous formulation of captopril at 1 mg/ml. Farm Hosp. 2005;29(1):30-6.
http://www.ncbi.nlm.nih.gov/pubmed/15773800
10. Misík V et al, Reactions of captopril and epicaptopril with transition metal ions and hydroxyl radicals: an EPR spectroscopy study. Free Radic Biol Med. 1993;15(6):611-9.
http://dx.doi.org/10.1016/0891-5849(93)90164-P
11. Mueller SA, Driscoll WJ, Mueller GP, Captopril inhibits peptidylglycine- alpha-hydroxylating monooxygenase: implications for therapeutic effects. Pharmacology. 1999;58(5):270-80.
http://dx.doi.org/10.1159/000028290
12. Spotheim-Maurizot M et al, N-acetylcysteine and captopril protect DNA and cells against radiolysis by fast neutrons. Radiat Environ Biophys. 1993;32(4):337-43.
http://dx.doi.org/10.1007/BF01225921
13. Remko M et al, Molecular structure and acidity of captopril, zofenopril and their metabolites captopril disulfide and zofenoprilat. Computational and Theoretical Chemistry 2015;1062:50–55.
http://dx.doi.org/10.1016/j.comptc.2015.03.025
14. Chopra M et al, Captopril: a free radical scavenger. Br J Clin Pharmacol. 1989; 27(3): 396–399.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1379842/
15. Sorbi D et al, Captopril inhibits the 72 kDa and 92 kDa matrix metalloproteinases. Kidney Int. 1993;44(6):1266-72.
http://dx.doi.org/10.1038/ki.1993.378
16. Bagchi D, Prasad R, Das DK, Direct scavenging of free radicals by captopril, an angiotensin converting enzyme inhibitor. Biochem Biophys Res Commun. 1989; 158(1):52-57.
http://dx.doi.org/10.1016/S0006-291X(89)80175-5
17. Day RM et al, Enhanced hematopoietic protection from radiation by the combination of genistein and captopril. Int Immunopharmacol. 2013;15(2):348-56.
http://dx.doi.org/10.1016/j.intimp.2012.12.029
18. Campbell BC, Shepherd AN, Reid JL, Effects of the angiotensin converting enzyme inhibitor, captopril, in essential hypertension. Br J Clin Pharmacol. 1982; 13(2): 213–217.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1401997/
19. Lapenna D et al, The prooxidant properties of captopril. Biochemical Pharmacology 1995; 50(1):27–32.
http://dx.doi.org/10.1016/0006-2952(95)00102-6
20. Hosseinimehr SJ, Mahmoudzadeh A, Akhlagpour S, Captopril protects mice bone marrow cells against genotoxicity induced by gamma irradiation. Cell Biochem Funct. 2007;25(4):389-94.
http://dx.doi.org/10.1027/cbf.1311
21. al-Harbi MM, Effect of captopril on the cytological and biochemical changes induced by adriamycin. Food Chem Toxicol. 1993;31(3):209-12.
http://dx.doi.org/10.1016/0278-6915(93)90095-G
22. Assyag P et al, Agranulocytosis caused by captopril. Ann Cardiol Angeiol (Paris). 1987;36(2):81-3.
http://www.ncbi.nlm.nih.gov/pubmed/3548568
23. Kilgore KS et al, Sulfhydryl compounds, captopril, and MPG inhibit complement-mediated myocardial injury. Am J Physiol. 1994;266(1 Pt 2):H28-35.
http://www.ncbi.nlm.nih.gov/pubmed/8304510
24. Cohen EP, Fish BL, Moulder JE, Treatment of radiation nephropathy with captopril. Radiat Res. 1992;132(3):346-50.
http://dx.doi.org/10.2307/3578243
25. Izzo JL Jr, Weir MR, Angiotensin-converting enzyme inhibitors. J Clin Hypertens (Greenwich). 2011;13(9):667-75.
http://dx.doi.org/10.1111/j.1751-7176.2011.00508.x
26. Parving HH, Hommel E, Smidt UM, Protection of kidney function and decrease in albuminuria by captopril in insulin dependent diabetics with nephropathy. BMJ. 1988; 297(6656): 1086–1091.
http://dx.doi.org/10.1136/bmj.297.6656.1086
27. Sloand JA, Izzo JL Jr, Captopril reduces urinary cystine excretion in cystinuria. Arch Intern Med. 1987;147(8):1409-12.
http://dx.doi.org/10.1001/archinte.1987.00370080045011
28. Westlin W, Mullane K, Does captopril attenuate reperfusion-induced myocardial dysfunction by scavenging free radicals? Circulation. 1988;77(6 Pt 2):I30-9.
http://www.ncbi.nlm.nih.gov/pubmed/2836109
29. Freedman AM, Cassidy MM, Weglicki WB, Captopril protects against myocardial injury induced by magnesium deficiency. Hypertension. 1991;18(2):142-7.
http://dx.doi.org/10.1161/01.HYP.18.2.142
30. Goldschmidt JE, Tallarida RJ, Pharmacological evidence that captopril possesses an endothelium-mediated component of vasodilation: effect of sulfhydryl groups on endothelium-derived relaxing factor. J Pharmacol Exp Ther. 1991;257(3):1136-45.
http://www.ncbi.nlm.nih.gov/pubmed/1646324
31. Vogt B, Frey FJ, Inhibition of angiogenesis in Kaposi's sarcoma by captopril. Lancet. 1997;349(9059):1148.
http://dx.doi.org/10.1016/S0140-6736(05)63025-5
32. Liu HM, Guo YN, Effect of captopril on serum TNF-α level in acute lung injury rats induced by HCL. Asian Pac J Trop Med. 2014;7(11):905-8.
http://dx.doi.org/10.1016/S1995-7645(14)60158-9
33. Chobanian AV et al, Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension. 1990;15(3):327-31.
http://dx.doi.org/10.1161/01.HYP.15.3.327
34. Constantinescu CS, Goodman DB, Ventura ES, Captopril and lisinopril suppress production of interleukin-12 by human peripheral blood mononuclear cells. Immunol Lett. 1998;62(1):25-31.
http://dx.doi.org/10.1016/S0165-2478(98)00025-X
35. Volpert OV et al, Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats. J Clin Invest. 1996;98(3):671-9.
http://dx.doi.org/10.1172/JCI118838
36. Moulder JE, Fish BL, Cohen EP, Angiotensin II receptor antagonists in the treatment and prevention of radiation nephropathy. Int J Radiat Biol. 1998;73(4):415-21.
http://dx.doi.org/10.1080/095530098142257
37. Medhora M et al, Radiation damage to the lung: mitigation by angiotensin converting enzyme (ACE) inhibitors. Respirology. 2012; 17(1): 66–71.
http://dx.doi.org/10.1111/j.1440-1843.2011.02092.x
38. de Groot-Besseling RR et al, Anti-tumor activity of a combination of plasminogen activator and captopril in a human melanoma xenograft model. Int J Cancer. 2004;112(2):329-34.
http://dx.doi.org/10.1002/ijc.20400
39. Antonaccio MJ, McGill M, Comparative effects of captopril and MK 421 on sympathetic function in spontaneously hypertensive rats. Am J Cardiol. 1982;49(6):1533-4.
http://dx.doi.org/10.1016/0002-9149(82)90379-4
40. Heel RC et al, Captopril: a preliminary review of its pharmacological properties and therapeutic efficacy. Drugs. 1980;20(6):409-52.
http://dx.doi.org/10.2165/00003495-198020060-00001
41. Drummer OH, Jarrott B, The Disposition and Metabolism of Captopril. Medicinal Research Reviews 1986; 6(1):75-97.
http://dx.doi.org/10.1002/med.2610060104
42. Murthy VS et al, Inhibition of angiotensin converting enzyme by SQ 14,225 in conscious rabbits. Eur J Pharmacol. 1977;46(3):207-12.
http://dx.doi.org/10.1016/0014-2999(77)90335-1
43. Rooprai HK et al,Evaluation of the effects of swainsonine, captopril, tangeretin and nobiletin on the biological behaviour of brain tumour cells in vitro. Neuropathol Appl Neurobiol. 2001;27(1):29-39.
http://dx.doi.org/10.1046/j.0305-1846.2000.00298.x
44. Lever AF et al, Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet. 1998;352(9123):179-84.
http://dx.doi.org/10.1016/S0140-6736(98)03228-0
45. Hardy LW, Malikayil A, The impact of structure-guided drug design on clinical agents. www.currentdrugdiscovery.com 2003:15-20.
http://hod4.net/~hod/papers/General/structure-guided_drug_design.pdf