Captopril, sold under the brand nameCapoten among others, is anangiotensin-converting enzyme (ACE) inhibitor used for the treatment ofhypertension and some types ofcongestive heart failure. Captopril was the first oral ACE inhibitor found for the treatment of hypertension.[2] It does not cause fatigue as associated with beta-blockers.
Captopril was patented in 1976 and approved for medical use in 1980.[3]
Captopril has an L-proline group which allows it to be more bioavailable in oral formulations. The thiol moiety within the molecule has been associated with two significant 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 includes hives, severe stomach pain, difficulty breathing, and swelling of the face, lips, tongue or throat.[4]
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.
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.[6]
It has also been investigated for use in the treatment of cancer.[7] Captopril stereoisomers were also reported to inhibit some metallo-β-lactamases.[8]
Adverse effects of captopril include cough due to increase in the plasma levels of bradykinin,angioedema,agranulocytosis,proteinuria,hyperkalemia,taste alteration,teratogenicity,postural hypotension,acute renal failure, andleukopenia.[9]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.Hyperkalemia can occur, especially if used with other drugs which elevate potassium level in blood, such as potassium-sparingdiuretics. Other side effects are:
Theadverse drug reaction (ADR) profile of captopril is similar to otherACE inhibitors, with cough being the most common ADR.[10] However, captopril is also commonly associated with rash and taste disturbances (metallic or loss of taste), which are attributed to the uniquethiol moiety.[11]
In the late 1960s,John Vane of theRoyal College of Surgeons of England was working on mechanisms by which the body regulates blood pressure.[15] He was joined bySérgio 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 ofangiotensin-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 (nowBristol-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.[3] 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.[16][17] In the 1980s, Vane received the Nobel prize and was knighted for his work and Ferreira received theNational Order of Scientific Merit from Brazil.
The development of captopril was among the earliest successes of the revolutionary concept ofstructure-baseddrug design.[18] Therenin–angiotensin–aldosterone system had been extensively studied in the mid-20th century, and this system presented several opportune targets in the development of novel treatments for hypertension. The first two targets that were attempted wererenin andACE. 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 byJohn Vane at theRoyal College of Surgeons of England. The first breakthrough was made by Kevin K.F. Ng[19][20][21] in 1967, when he found the conversion of angiotensin I to angiotensin II took place in thepulmonary circulation instead of in theplasma. In contrast,Sergio Ferreira[22] 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, usingbradykinin potentiating factor (BPF) provided by Sergio Ferreira,[23] 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 viaQSAR-based modification that the terminal sulfhydryl moiety of the peptide provided a high potency ofACE inhibition.[24]
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.
A chemical synthesis of captopril by treatment ofL-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.[25]
Captopril synthesis 1
Captopril synthesis 2
Captopril synthesis of Shimazaki, Watanabe, et al.
Unlike the majority of ACE inhibitors, captopril is not administered as a prodrug (the only other beinglisinopril).[33] About 70% of orally administered captopril is absorbed.Bioavailability is reduced by presence of food in stomach. It is partly metabolised and partly excreted unchanged inurine.[34] Captopril also has a relatively poor pharmacokinetic profile. The shorthalf-life necessitates dosing two or three times per day, which may reduce patientcompliance. Captopril has a short half-life of 2–3 hours and a duration of action of 12–24 hours.
^Vidt DG, Bravo EL, Fouad FM (January 1982). "Medical intelligence drug therapy: captopril".The New England Journal of Medicine.306 (4):214–219.doi:10.1056/nejm198201283060405.PMID7033784.
^Akif M, Georgiadis D, Mahajan A, Dive V, Sturrock ED, Isaac RE, Acharya KR (July 2010). "High-resolution crystal structures of Drosophila melanogaster angiotensin-converting enzyme in complex with novel inhibitors and antihypertensive drugs".Journal of Molecular Biology.400 (3):502–517.doi:10.1016/j.jmb.2010.05.024.PMID20488190.
^Nelson L, Howland MA, Lewin NA, Smith SW, Goldfrank R, Hoffman RS, Flomenbaum N (2019).Goldfrank's toxicologic emergencies. New York: McGraw-Hill Education. p. 953.ISBN978-1-259-85961-8.
^Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs, Jeffrey K. Aronson, page 120.
^Ajayi AA, Campbell BC, Rubin PC, Reid JL (November 1985). "Effect of naloxone on the actions of captopril".Clinical Pharmacology and Therapeutics.38 (5):560–565.doi:10.1038/clpt.1985.224.PMID2996820.S2CID35799800.
^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 toE.R. Squibb & Sons Inc.
^Ondetti MA, Rubin B, Cushman DW (April 1977). "Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents".Science.196 (4288):441–444.Bibcode:1977Sci...196..441O.doi:10.1126/science.191908.PMID191908.
^Cushman DW, Cheung HS, Sabo EF, Ondetti MA (December 1977). "Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids".Biochemistry.16 (25):5484–5491.doi:10.1021/bi00644a014.PMID200262.
^Vallerand AH, Sanoski CA, Deglin JH (2014-06-05).Davis's drug guide for nurses (Fourteenth ed.). Philadelphia: F. A. Davis Company.ISBN978-0-8036-4085-6.OCLC881473728.
^Duchin KL, McKinstry DN, Cohen AI, Migdalof BH (April 1988). "Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases".Clinical Pharmacokinetics.14 (4):241–259.doi:10.2165/00003088-198814040-00002.PMID3292102.S2CID46614471.
