Captopril

Source: Wikipedia, the free encyclopedia.
Captopril
Clinical data
Pronunciation/ˈkæptəprɪl/
Trade namesCapoten, others
AHFS/Drugs.comMonograph
MedlinePlusa682823
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • US: WARNING[1]
  • EU: Rx-only[2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability70–75%
MetabolismLiver
Elimination half-life1.9 hours
ExcretionKidney
Identifiers
  • (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid
JSmol)
  • O=C(O)[C@H]1N(C(=O)[C@H](C)CS)CCC1
  • 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 checkY
  • Key:FAKRSMQSSFJEIM-RQJHMYQMSA-N checkY
  (verify)

Captopril, sold under the brand name Capoten among others, is an

congestive heart failure. Captopril was the first oral ACE inhibitor found for the treatment of hypertension.[3]
It does not cause fatigue as associated with beta-blockers. Due to the adverse drug event of causing hyperkalemia, as seen with most ACE Inhibitors, the medication is usually paired with a diuretic.

Captopril was patented in 1976 and approved for medical use in 1980.[4]

Structure–activity relationship

Captopril has an L-proline group which allows for it to be more bioavailable within oral formulations. The thiol moiety within the molecule has been associated with two significance adverse effects: the hapten or immune response. This immune response, also known as agranulocytosis, can explain the adverse drug events which may be seen in captopril with the allergic response, which would be: hives, severe stomach pain, difficulty breathing, swelling of the face, lips, tongue or throat.[5]

In terms of interaction with the enzyme, the molecule's thiol moiety will attach to the binding site of the ACE enzyme. This will inhibit the port at which the angiotensin-1 molecule would normally bind, therefore inhibiting the downstream effects within the renin-angiotensin system.

Medical uses

Drosophila ACE in complex with captopril (purple), PDB entry 2x8z[6]

Captopril's main uses are based on its vasodilation and inhibition of some renal function activities. These benefits are most clearly seen in:

Additionally, it has shown mood-elevating properties in some patients. This is consistent with the observation that animal screening models indicate putative antidepressant activity for this compound, although one study has been negative. Formal clinical trials in depressed patients have not been reported.[7]

It has also been investigated for use in the treatment of cancer.[8] Captopril stereoisomers were also reported to inhibit some metallo-β-lactamases.[9]

Adverse effects

Main article: ACE inhibitor § Adverse effects

Adverse effects of captopril include cough due to increase in the plasma levels of bradykinin,

acute renal failure, and leukopenia.[10]
Except for postural hypotension, which occurs due to the short and fast mode of action of captopril, most of the side effects mentioned are common for all ACE inhibitors. Among these, cough is the most common adverse effect.
diuretics
. Other side effects are:

The adverse drug reaction (ADR) profile of captopril is similar to other ACE inhibitors, with cough being the most common ADR.[11] However, captopril is also commonly associated with rash and taste disturbances (metallic or loss of taste), which are attributed to the unique thiol moiety.[12]

Overdose

ACE inhibitor

overdose can be treated with naloxone.[13][14][15]

History

In the late 1960s, John Vane of the Royal College of Surgeons of England was working on mechanisms by which the body regulates blood pressure.[16] He was joined by Sérgio Henrique Ferreira of Brazil, who had been studying the venom of a Brazilian pit viper, the jararaca (Bothrops jararaca), and brought a sample of the viper's venom. Vane's team found that one of the venom's peptides selectively inhibited the action of angiotensin-converting enzyme (ACE), which was thought to function in blood pressure regulation; the snake venom functions by severely depressing blood pressure. During the 1970s, ACE was found to elevate blood pressure by controlling the release of water and salts from the kidneys.

Captopril, an analog of the snake venom's ACE-inhibiting peptide, was first synthesized in 1975 by three researchers at the U.S. drug company E.R. Squibb & Sons Pharmaceuticals (now

Bristol-Myers Squibb): Miguel Ondetti, Bernard Rubin, and David Cushman. Squibb filed for U.S. patent protection on the drug in February 1976, which was granted in September 1977, and captopril was approved for medical use in 1980.[4] It was the first ACE inhibitor developed and was considered a breakthrough both because of its mechanism of action and also because of the development process.[17][18] In the 1980s, Vane received the Nobel prize and was knighted for his work and Ferreira received the National Order of Scientific Merit
from Brazil.

The development of captopril was among the earliest successes of the revolutionary concept of

ACE
. Captopril was the culmination of efforts by Squibb's laboratories to develop an ACE inhibitor.

Ondetti, Cushman, and colleagues built on work that had been done in the 1960s by a team of researchers led by John Vane at the Royal College of Surgeons of England. The first breakthrough was made by Kevin K.F. Ng[20][21][22] in 1967, when he found the conversion of angiotensin I to angiotensin II took place in the pulmonary circulation instead of in the plasma. In contrast, Sergio Ferreira[23] found bradykinin disappeared in its passage through the pulmonary circulation. The conversion of angiotensin I to angiotensin II and the inactivation of bradykinin were thought to be mediated by the same enzyme.

In 1970, using

bradykinin potentiating factor (BPF) provided by Sergio Ferreira,[24] Ng and Vane found the conversion of angiotensin I to angiotensin II was inhibited during its passage through the pulmonary circulation. BPF was later found to be a peptide in the venom of a lancehead viper (Bothrops jararaca), which was a “collected-product inhibitor” of the converting enzyme. Captopril was developed from this peptide after it was found via QSAR-based modification that the terminal sulfhydryl moiety of the peptide provided a high potency of ACE inhibition.[25]

Captopril gained FDA approval on April 6, 1981. The drug became a generic medicine in the U.S. in February 1996, when the market exclusivity held by Bristol-Myers Squibb for captopril expired.

Chemical synthesis

A chemical synthesis of captopril by treatment of L-proline with (2S)-3-acetylthio-2-methylpropanoyl chloride under basic conditions (NaOH), followed by aminolysis of the protective acetyl group to unmask the drug's free thiol, is depicted in the figure at right.[26]

Captopril synthesis 1 Captopril synthesis 2
Captopril synthesis of Shimazaki, Watanabe, et al.
Patents:[27][28][29] Design and synthesis:[30][31] Improved synthesis:[32]

Procedure 2 taken out of patent US4105776. See examples 28, 29a and 36.

Mechanism of action

Captopril blocks the conversion of angiotensin I to angiotensin II and prevents the degradation of vasodilatory prostaglandins, thereby inhibiting vasoconstriction and promoting systemic vasodilation.[33]

Pharmacokinetics

Unlike the majority of ACE inhibitors, captopril is not administered as a prodrug (the only other being

compliance
. Captopril has a short half-life of 2–3 hours and a duration of action of 12–24 hours.

See also

References

  1. FDA
    . Retrieved 22 Oct 2023.
  2. ^ "List of nationally authorised medicinal products Active substance: captopril" (PDF). ema.europa.eu. European Medicines Agency. 26 November 2020. Archived from the original (PDF) on 31 October 2021.
  3. PMID 7033784
    .
  4. ^
    ISBN 978-3-527-60749-5
    .
  5. ^ "Captopril: Uses, Dosage, Side Effects". Drugs.com. Retrieved 2021-10-31.
  6. PMID 20488190
    .
  7. ISBN 978-0-7817-0166-2
    .
  8. S2CID 24210204
    .
  9. PMID 26482303
    .
  10. ^ "Captopril (ACE inhibitor): side effects". lifehugger. 2008-07-09. Archived from the original on 2009-08-14. Retrieved 2009-05-02.
  11. ^ Rossi S, ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook.
  12. S2CID 32209360
    .
  13. ISBN 978-1-259-85961-8
    .
  14. ^ Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs, Jeffrey K. Aronson, page 120.
  15. S2CID 35799800
    .
  16. ^ Crow JM. "Drugs with bite: The healing powers of venoms". New Scientist. Retrieved 2020-07-30.
  17. ^ Bryan J (2009). "From snake venom to ACE inhibitor the discovery and rise of captopril". Pharmaceutical Journal. Retrieved 2015-01-08.
  18. doi:10.1002/jps.2600740942
    .
  19. PMID 200262
    .
  20. S2CID 4289093
    .
  21. S2CID 4174541
    .
  22. S2CID 4200012
    .
  23. PMID 6036419
    .
  24. S2CID 45232683
    .
  25. S2CID 1045315
    .
  26. doi:10.1248/cpb.30.3139
    .
  27. ^ DE 2703828, Cushman DW, Ondetti MA, "Prolinderivate und verwandte Verbindungen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel [Proline derivatives and related compounds, methods for their manufacturing and their use as a medicinal product]", published 1977-08-18, assigned to E.R. Squibb & Sons Inc. 
  28. ^ US 4046889, Ondetti MA, Cushman DW, issued 1977, assigned to Squibb 
  29. ^ US 4105776, Ondetti MA, Cushman DW, issued 1978, assigned to Squibb 
  30. PMID 191908
    .
  31. PMID 200262
    .
  32. PMID 6396401
    .
  33. OCLC 881473728
    .
  34. PMID 9577953
    .
  35. S2CID 46614471
    .

External links
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