Browse history interactively

Page 1

Page 1Revision 1

Page 2

Page 2Revision 2

← Previous editContent deleted Content addedVisualWikitext

Revision as of 09:00, 25 October 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank').← Previous edit		Latest revision as of 21:19, 18 October 2024 edit undoAnomieBOT (talk | contribs)Bots6,570,988 editsm Dating maintenance tags: {{Citation needed}}
(195 intermediate revisions by more than 100 users not shown)
Line 1:		Line 1:
			{{Short description|Antihypertensive drug of the ACE inhibitor class}}
	{{drugbox | Verifiedfields = changed
			{{drugbox | Watchedfields = changed
	| verifiedrevid = 401601651
			| verifiedrevid = 457287479
	| IUPAC_name = (''2S'')-1-<nowiki></nowiki><br />pyrrolidine-2-carboxylic acid
			| IUPAC_name = (2''S'')-1-pyrrolidine-2-carboxylic acid
	| image = Captopril.svg
			| image = Captopril structure.svg
	| width = 160
			| width = 222
	| image2 = Captopril-3D-vdW.png
			| alt =
			| image2 = File:Captopril-from-xtal-1980-3D-balls.png
			| alt2 =
	<!--Clinical data-->		<!--Clinical data-->
	| tradename = Capoten		| tradename = Capoten, others
	| Drugs.com = {{drugs.com|monograph|captopril}}		| Drugs.com = {{drugs.com|monograph|captopril}}
			| pronounce = {{IPAc-en|ˈ|k|æ|p|t|ə|p|r|ɪ|l}}
	| MedlinePlus = a682823		| MedlinePlus = a682823
	| pregnancy_AU = D		| pregnancy_AU = D
			| pregnancy_category =
	| pregnancy_US =
			| routes_of_administration = ]
	| pregnancy_category =
			| ATC_prefix = C09
			| ATC_suffix = AA01
			| legal_EU = Rx-only
			| legal_EU_comment = <ref>{{cite web |title=List of nationally authorised medicinal products Active substance: captopril |url=https://www.ema.europa.eu/en/documents/psusa/captopril-list-nationally-authorised-medicinal-products-psusa/00000535/202004_en.pdf |website=ema.europa.eu |publisher=European Medicines Agency |archive-url=https://web.archive.org/web/20211031171542/https://www.ema.europa.eu/en/documents/psusa/captopril-list-nationally-authorised-medicinal-products-psusa/00000535/202004_en.pdf |archive-date=31 October 2021 |language=en |date=26 November 2020 |url-status=dead}}</ref>
	| legal_status = Rx-only		| legal_status = Rx-only
	| routes_of_administration = oral
	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
	| bioavailability = 70–75%		| bioavailability = 70–75%
	| metabolism = ]		| metabolism = ]
	| elimination_half-life = 1.9 hours		| elimination_half-life = 1.9 hours
	| excretion = ]		| excretion = ]
	<!--Identifiers-->		<!--Identifiers-->
			| IUPHAR_ligand = 5158
	| CASNo_Ref = {{cascite|correct|CAS}}
	| CAS_number_Ref = {{cascite|correct|??}}		| CAS_number_Ref = {{cascite|correct|??}}
	| CAS_number = 62571-86-2		| CAS_number = 62571-86-2
	| ATC_prefix = C09
	| ATC_suffix = AA01
	| PubChem = 44093		| PubChem = 44093
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
Line 35:		Line 41:
	| UNII_Ref = {{fdacite|correct|FDA}}		| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = 9G64RSX1XD		| UNII = 9G64RSX1XD
	| KEGG_Ref = {{keggcite|changed|kegg}}		| KEGG_Ref = {{keggcite|correct|kegg}}
	| KEGG = D00251		| KEGG = D00251
	| ChEBI_Ref = {{ebicite|changed|EBI}}		| ChEBI_Ref = {{ebicite|correct|EBI}}
	| ChEBI = 3380		| ChEBI = 3380
	| ChEMBL_Ref = {{ebicite|changed|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 1560		| ChEMBL = 1560
			| PDB_ligand = X8Z
	<!--Chemical data-->		<!--Chemical data-->
	| C=9 | H=15 | N=1 | O=3 | S=1		| C=9 | H=15 | N=1 | O=3 | S=1
	| molecular_weight = 217.29
	| smiles = O=C(O)1N(C(=O)(C)CS)CCC1		| smiles = O=C(O)1N(C(=O)(C)CS)CCC1
	| InChI = 1/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
	| InChIKey = FAKRSMQSSFJEIM-RQJHMYQMBT
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 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		| StdInChI = 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
Line 53:		Line 57:
	| StdInChIKey = FAKRSMQSSFJEIM-RQJHMYQMSA-N		| StdInChIKey = FAKRSMQSSFJEIM-RQJHMYQMSA-N
	}}		}}
	'''Captopril''' (]) ({{IPAc-en|icon|ˈ|k|æ|p|t|ə|p|r|ɪ|l}}) is an ] inhibitor (]) used for the treatment of ] and some types of ]. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the revolutionary development process. Captopril is commonly marketed by ] under the ] '''Capoten'''.
			<!-- Definition and medical uses -->
	==Clinical use==
			'''Captopril''', sold under the brand name '''Capoten''' among others, is an ] used for the treatment of ] and some types of ]. Captopril was the first oral ACE inhibitor found for the treatment of hypertension.<ref>{{cite journal | vauthors = Vidt DG, Bravo EL, Fouad FM | title = Medical intelligence drug therapy: captopril | language = EN | journal = The New England Journal of Medicine | volume = 306 | issue = 4 | pages = 214–219 | date = January 1982 | pmid = 7033784 | doi = 10.1056/nejm198201283060405 }}</ref> 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.{{Citation needed|date=October 2024}}
	Captopril's main uses are based on its vasodilation and inhibition of some renal function activities. These benefits are most clearly seen in the following conditions:
			Captopril was patented in 1976 and approved for medical use in 1980.<ref name="Fis2006">{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=467 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA467 |language=en}}</ref>
	1) ]
			== Structure–activity relationship ==
	2) Cardiac conditions such as post ] and ]
			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, swelling of the face, lips, tongue or throat.<ref>{{Cite web|title=Captopril: Uses, Dosage, Side Effects|url=https://www.drugs.com/captopril.html|access-date=2021-10-31|website=Drugs.com|language=en}}</ref>
			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.
	3) Preservation of kidney function in ]
			==Medical uses==
	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 there has been one negative study. Formal clinical trials in depressed patients have not been reported.<ref></ref>
			]
			Captopril's main uses are based on its vasodilation and inhibition of some renal function activities. These benefits are most clearly seen in:
			* ]
			* Cardiac conditions such as ] and after ]
			* Preservation of kidney function 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.<ref>{{cite book | vauthors = Murphy DL, Mitchell PB, Potter WZ | chapter = Novel Pharmacological Approaches to the Treatment of Depression | chapter-url = https://acnp.org/g4/GN401000109/Default.htm | date = 1995 | veditors = Bloom FE, Kupfer DJ | title = Psychopharmacology | edition = The Fourth Generation of Progress | publisher = Raven Press | isbn = 978-0-7817-0166-2 | pages = 1143–1153 }}</ref>
	It has also been investigated for use in the treatment of cancer.<ref name="pmid18837885">{{cite journal |author=Attoub S, Gaben AM, Al-Salam S, ''et al.'' |title=Captopril as a potential inhibitor of lung tumor growth and metastasis |journal=Ann. N. Y. Acad. Sci. |volume=1138 |issue= |pages=65–72 |year=2008 |month=September |pmid=18837885 |doi=10.1196/annals.1414.011 |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2008&volume=1138&spage=65}}</ref>
			It has also been investigated for use in the treatment of cancer.<ref name="pmid18837885">{{cite journal | vauthors = Attoub S, Gaben AM, Al-Salam S, Al Sultan MA, John A, Nicholls MG, Mester J, Petroianu G | display-authors = 6 | title = Captopril as a potential inhibitor of lung tumor growth and metastasis | journal = Annals of the New York Academy of Sciences | volume = 1138 | issue = 1 | pages = 65–72 | date = September 2008 | pmid = 18837885 | doi = 10.1196/annals.1414.011 | bibcode = 2008NYASA1138...65A| s2cid = 24210204 }}</ref> Captopril stereoisomers were also reported to inhibit some metallo-].<ref>{{cite journal | vauthors = Brem J, van Berkel SS, Zollman D, Lee SY, Gileadi O, McHugh PJ, Walsh TR, McDonough MA, Schofield CJ | display-authors = 6 | title = Structural Basis of Metallo-β-Lactamase Inhibition by Captopril Stereoisomers | journal = Antimicrobial Agents and Chemotherapy | volume = 60 | issue = 1 | pages = 142–150 | date = January 2016 | pmid = 26482303 | pmc = 4704194 | doi = 10.1128/AAC.01335-15 }}</ref>
	==History==
	Captopril was developed in 1975 by three researchers at the ] drug company Squibb (now ]): Miguel Ondetti, Bernard Rubin and David Cushman. Squibb filed for U.S. patent protection on the drug in February 1976 and U.S. Patent 4,046,889 was granted in September 1977.
			==Adverse effects==
	The development of captopril was amongst the earliest successes of the revolutionary concept of structure-based drug design. The ] system had been extensively studied in the mid-20th century and it had been decided that this system presented several opportune targets in the development of novel treatments for hypertension. The first two targets that were attempted were ] and ]. Captopril was the culmination of efforts by Squibb's laboratories to develop an ACE inhibitor.
			{{Main|ACE inhibitor#Adverse effects}}
			Adverse effects of captopril include cough due to increase in the plasma levels of bradykinin, ], ], ], ], ], ]icity, ], ], and ].<ref name="captopril adverse effects">{{cite web|url=http://mc.lifehugger.com/moc/157/captopril-ace-inhibitor-side-effects |archive-url=https://archive.today/20090814010520/http://mc.lifehugger.com/moc/157/captopril-ace-inhibitor-side-effects |url-status=dead |archive-date=2009-08-14 |title=Captopril (ACE inhibitor): side effects |date=2008-07-09 |publisher=lifehugger |access-date=2009-05-02 }}</ref>
	Ondetti, Cushman and colleagues built on work that had been done in the 1960s by a team of researchers led by ] at the Royal College of Surgeons of England. The first breakthrough was made by Kevin K.F.Ng<ref>Ng KKF and Vane JR: Conversion of angiotensin I to angiotensin II. Nature 1967, 216, 762-766.</ref><ref>Ng KKF and Vane JR: Fate of angiotensin I in the circulation. Nature, 1968, 218, 144-150.</ref><ref>Ng KKF and Vane JR: Some properties of angiotensin converting enzyme in the lung in vivo. Nature, 1970, 225, 1142-1144.</ref> in 1967 when he found that the conversion of angiotensin I to angiotensin II took place in the pulmonary circulation instead of in the plasma. In contrast, ]<ref>Ferreira SH and Vane JR: The disappearance of bradykinin and eledoisin in the circulation and vascular beds of the cat. Br. J. Pharm. Chemother.,1967,30, 417-424.</ref> found that bradykinin disappeared in its passage through the pulmonary circulation. The conversion of angiotensin I to angiotensin II and the inactivation of bradykinin was thought to be mediated by the same enzyme.
			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. ] can occur, especially if used with other drugs which elevate potassium level in blood, such as potassium-sparing ]. Other side effects are:
			* ]
	In 1970, using ] (BPF) provided by Sergio Ferreira,<ref name="pmid12724335">{{cite journal |author=Smith CG, Vane JR |title=The discovery of captopril |journal=FASEB J. |volume=17 |issue=8 |pages=788–9 |year=2003 |month=May |pmid=12724335 |doi=10.1096/fj.03-0093life |url=http://www.fasebj.org/cgi/pmidlookup?view=long&pmid=12724335}}</ref> Ng and Vane found that 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 pit viper ''(])'' venom 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 ].
			* ]
			* ]
			* ]
			* ]
			* ]
			* ]
			The ] (ADR) profile of captopril is similar to other ]s, with cough being the most common ADR.<ref>{{cite book | veditors = Rossi S | title = Australian Medicines Handbook | title-link = Australian Medicines Handbook | location = Adelaide | publisher = Australian Medicines Handbook | date = 2006 }}</ref> However, captopril is also commonly associated with rash and taste disturbances (metallic or loss of taste), which are attributed to the unique ] moiety.<ref>{{cite journal | vauthors = Atkinson AB, Robertson JI | title = Captopril in the treatment of clinical hypertension and cardiac failure | journal = Lancet | volume = 2 | issue = 8147 | pages = 836–839 | date = October 1979 | pmid = 90928 | doi = 10.1016/S0140-6736(79)92186-X | s2cid = 32209360 }}</ref>
	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.
			==Overdose==
	The development of captopril has been claimed as an instance of 'biopiracy' (]), since no benefits have flowed back to the indigenous Brazilian tribe who first used pit viper venom as an arrowhead poison.<ref> </ref>
			ACE inhibitor ] can be treated with ].<ref>{{cite book | vauthors = Nelson L, Howland MA, Lewin NA, Smith SW, Goldfrank R, Hoffman RS, Flomenbaum N | title = Goldfrank's toxicologic emergencies | location = New York | publisher = McGraw-Hill Education | date = 2019 | page = 953 | isbn = 978-1-259-85961-8 }}</ref><ref>Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs, Jeffrey K. Aronson, page 120.</ref><ref>{{cite journal | vauthors = Ajayi AA, Campbell BC, Rubin PC, Reid JL | title = Effect of naloxone on the actions of captopril | journal = Clinical Pharmacology and Therapeutics | volume = 38 | issue = 5 | pages = 560–565 | date = November 1985 | pmid = 2996820 | doi = 10.1038/clpt.1985.224 | s2cid = 35799800 }}</ref>
			==History==
	]
			In the late 1960s, ] of the ] was working on mechanisms by which the body regulates blood pressure.<ref>{{Cite web| vauthors = Crow JM |title=Drugs with bite: The healing powers of venoms|url=https://www.newscientist.com/article/dn21775-drugs-with-bite-the-healing-powers-of-venoms/|access-date=2020-07-30|website=New Scientist|language=en-US}}</ref> He was joined by ] of Brazil, who had been studying the venom of a Brazilian pit viper, the 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 ] (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 ]): 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.<ref name="Fis2006" /> 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.<ref>{{cite journal| vauthors = Bryan J |year=2009|title=From snake venom to ACE inhibitor the discovery and rise of captopril|url=http://www.pharmaceutical-journal.com/news-and-analysis/news/from-snake-venom-to-ace-inhibitor-the-discovery-and-rise-of-captopril/10884359.article|journal=Pharmaceutical Journal|access-date=2015-01-08|name-list-style=vanc}}</ref><ref>{{cite journal | vauthors = Blankley CJ | title = Chronicals of Drug Discovery, vol. 2. | journal = Journal of Pharmaceutical Sciences | date = September 1985 | volume = 74 | issue = 9 | pages = 1029–1030 |doi=10.1002/jps.2600740942 }}</ref> In the 1980s, Vane received the Nobel prize and was knighted for his work and Ferreira received the ] from Brazil.
	==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.<ref>Shimazaki, M.; Hasegawa, J.; Kan, K.; Nomura, K.; Nose, Y.; Kondo, H.; Ohashi, T.; Watanabe, K. Chem. Pharm. Bull.1982, 30, 3139-3146.</ref>
			The development of captopril was among the earliest successes of the revolutionary concept of ]-based ].<ref>{{cite journal | vauthors = Cushman DW, Cheung HS, Sabo EF, Ondetti MA| title=Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids| url=https://pubs.acs.org/doi/10.1021/bi00644a014.article| journal=Biochemistry | date=December 1977| volume=16| issue=25| pages=5484–5491| pmid = 200262| doi = 10.1021/bi00644a014 | name-list-style=vanc }}</ref> The ] 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 were ] and ]. Captopril was the culmination of efforts by Squibb's laboratories to develop an ACE inhibitor.
	==Developments from captopril==
	===Limitations of captopril===
	The ] (ADR) profile of captopril is similar to other ]s, with cough being the most common ADR.<ref>Rossi S, editor. ] 2006. Adelaide: Australian Medicines Handbook; 2006.</ref> However, captopril is also commonly associated with rash and taste disturbances (metallic or loss of taste), which are attributed to the unique ] moiety.<ref>Atkinson AB, Robertson JIS. Captopril in the treatment of hypertension and cardiac failure. Lancet 1979;2(8147):836–9. PMID 90928</ref>
			Ondetti, Cushman, and colleagues built on work that had been done in the 1960s by a team of researchers led by ] at the ]. The first breakthrough was made by Kevin K.F. Ng<ref>{{cite journal | vauthors = Ng KK, Vane JR | title = Conversion of angiotensin I to angiotensin II | journal = Nature | volume = 216 | issue = 5117 | pages = 762–766 | date = November 1967 | pmid = 4294626 | doi = 10.1038/216762a0 | bibcode = 1967Natur.216..762N | s2cid = 4289093 }}</ref><ref>{{cite journal | vauthors = Ng KK, Vane JR | title = Fate of angiotensin I in the circulation | journal = Nature | volume = 218 | issue = 5137 | pages = 144–150 | date = April 1968 | pmid = 4296306 | doi = 10.1038/218144a0 | bibcode = 1968Natur.218..144N | s2cid = 4174541 }}</ref><ref>{{cite journal | vauthors = Ng KK, Vane JR | title = Some properties of angiotensin converting enzyme in the lung in vivo | journal = Nature | volume = 225 | issue = 5238 | pages = 1142–1144 | date = March 1970 | pmid = 4313869 | doi = 10.1038/2251142b0 | bibcode = 1970Natur.225.1142N | s2cid = 4200012 }}</ref> in 1967, when he found the conversion of angiotensin I to angiotensin II took place in the ] instead of in the ]. In contrast, ]<ref>{{cite journal | vauthors = Ferreira SH, Vane JR | title = The disappearance of bradykinin and eledoisin in the circulation and vascular beds of the cat | journal = British Journal of Pharmacology and Chemotherapy | volume = 30 | issue = 2 | pages = 417–424 | date = June 1967 | pmid = 6036419 | pmc = 1557274 | doi = 10.1111/j.1476-5381.1967.tb02148.x }}</ref> 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.
	Captopril also has a relatively poor pharmacokinetic profile. The short ] necessitates 2–3 times daily dosing, which may reduce patient ].
			In 1970, using ] (BPF) provided by Sergio Ferreira,<ref name="pmid12724335">{{cite journal | vauthors = Smith CG, Vane JR | title = The discovery of captopril | journal = FASEB Journal | volume = 17 | issue = 8 | pages = 788–789 | date = May 2003 | pmid = 12724335 | doi = 10.1096/fj.03-0093life | doi-access = free | s2cid = 45232683 }}</ref> 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 ''(])'', which was a “collected-product inhibitor” of the converting enzyme. Captopril was developed from this peptide after it was found via ] modification that the terminal sulfhydryl moiety of the peptide provided a high potency of ].<ref name="Patlak">{{cite journal | vauthors = Patlak M | title = From viper's venom to drug design: treating hypertension | journal = FASEB Journal | volume = 18 | issue = 3 | pages = 421 | date = March 2004 | pmid = 15003987 | doi = 10.1096/fj.03-1398bkt | doi-access = free | s2cid = 1045315 }}</ref>
	===Subsequent ACE inhibitors===
	The adverse effect and pharmacokinetic limitations of captopril stimulated the development ] and subsequent ACE inhibitors. These were specifically designed to lack the sulfhydryl moiety believed to be responsible for rash and taste disturbance.<ref>Patchett AA, Harris E, Tristam EQ, et al. A new class of angiotensin-converting enzyme inhibitors. Nature 1980;288(5788):280–3. PMID 6253826</ref> Most subsequent ACE inhibitors are given as ]s, to improve oral ]. All have a longer half-life and are given once or twice daily, which may improve patient compliance.
			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.
	==Adverse effects==
	{{dablink|Main article: ]}}
			==Chemical synthesis==
	Adverse effects of captopril include cough due to increase in the plasma levels of bradykinin, ], ], ], ], ], ]icity, ], [[acute renal failure|acute
			A chemical synthesis of captopril by treatment of <small>L</small>-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.<ref>{{cite journal | vauthors = Shimazaki M, Hasegawa J, Kan K, Nomura K, Nose Y, Kondo H, Ohashi T, Watanabe K | year = 1982 | volume = 30 | pages = 3139–3146 | journal = Chem. Pharm. Bull. | doi = 10.1248/cpb.30.3139 | title = Synthesis of captopril starting from an optically active .BETA.-hydroxy acid | issue = 9| doi-access = free }}</ref>
	renal failure]] and ].<ref name="captopril adverse effects">{{cite web|url=http://mc.lifehugger.com/moc/157/captopril-ace-inhibitor-side-effects|title=Captopril (ACE inhibitor): side effects|date=07-09-2008|publisher=lifehugger|accessdate=2009-05-02}}</ref>
			{| class="wikitable"
	Except for postural hypotension which occurs due to 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. ] can occur especially if used along with other drugs which elevate potassium level in blood like potassium sparing ].
			|-
			! Captopril synthesis 1 !! Captopril synthesis 2
			|-
			| ] || |pubdate=1977-08-18|assign=]| inventor= Cushman DW, Ondetti MA }}</ref><ref>{{cite patent | country = US | number = 4046889 | gdate = 1977 | inventor = Ondetti MA, Cushman DW | assign1 = Squibb }}</ref><ref>{{cite patent | country = US | number = 4105776 | gdate = 1978 | inventor = Ondetti MA, Cushman DW | assign1 = Squibb }}</ref> Design and synthesis:<ref>{{cite journal | vauthors = Ondetti MA, Rubin B, Cushman DW | title = Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents | journal = Science | volume = 196 | issue = 4288 | pages = 441–444 | date = April 1977 | pmid = 191908 | doi = 10.1126/science.191908 | bibcode = 1977Sci...196..441O }}</ref><ref>{{cite journal | vauthors = Cushman DW, Cheung HS, Sabo EF, Ondetti MA | title = Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids | journal = Biochemistry | volume = 16 | issue = 25 | pages = 5484–5491 | date = December 1977 | pmid = 200262 | doi = 10.1021/bi00644a014 }}</ref> Improved synthesis:<ref>{{cite journal | vauthors = Nam DH, Lee CS, Ryu DD | title = An improved synthesis of captopril | journal = Journal of Pharmaceutical Sciences | volume = 73 | issue = 12 | pages = 1843–1844 | date = December 1984 | pmid = 6396401 | doi = 10.1002/jps.2600731251 }}</ref>]]
			|}
			Procedure 2 taken out of patent US4105776. See examples 28, 29a and 36.
			==Mechanism of action==
			Captopril blocks the conversion of ] I to angiotensin II and prevents the degradation of vasodilatory ]s, thereby inhibiting ] and promoting systemic ].<ref>{{Cite book | vauthors = Vallerand AH, Sanoski CA, Deglin JH |title=Davis's drug guide for nurses |isbn=978-0-8036-4085-6 |edition=Fourteenth |location=Philadelphia |oclc=881473728 |date=2014-06-05|publisher=F. A. Davis Company}}</ref>
			==Pharmacokinetics==
			Unlike the majority of ACE inhibitors, captopril is not administered as a prodrug (the only other being ]).<ref>{{cite journal | vauthors = Brown NJ, Vaughan DE | title = Angiotensin-converting enzyme inhibitors | journal = Circulation | volume = 97 | issue = 14 | pages = 1411–1420 | date = April 1998 | pmid = 9577953 | doi = 10.1161/01.cir.97.14.1411 | doi-access = free }}</ref> About 70% of orally administered captopril is absorbed. ] is reduced by presence of food in stomach. It is partly metabolised and partly excreted unchanged in ].<ref>{{cite journal | vauthors = Duchin KL, McKinstry DN, Cohen AI, Migdalof BH | title = Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases | journal = Clinical Pharmacokinetics | volume = 14 | issue = 4 | pages = 241–259 | date = April 1988 | pmid = 3292102 | doi = 10.2165/00003088-198814040-00002 | s2cid = 46614471 }}</ref> Captopril also has a relatively poor pharmacokinetic profile. The short ] necessitates dosing two or three times per day, which may reduce patient ]. Captopril has a short half-life of 2–3 hours and a duration of action of 12–24 hours.
	==See also==		== See also ==
	*]		*]
	*]		*]
	==References==		== References ==
	{{reflist|2}}		{{Reflist}}
	==External links==		== External links ==
			* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/captopril | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Captopril }}
	* Captopril side effects:
	*		* {{Webarchive|url=https://web.archive.org/web/20190518001918/http://patimg2.uspto.gov/.piw?Docid=04046889&homeurl=http%3A%2F%2Fpatft.uspto.gov%2Fnetacgi%2Fnph-Parser%3FSect1%3DPTO2%2526Sect2%3DHITOFF%2526u%3D%2Fnetahtml%2Fsearch-adv.htm%2526r%3D1%2526p%3D1%2526f%3DG%2526l%3D50%2526d%3Dptxt%2526S1%3D4,046,889.WKU.%2526OS%3Dpn%2F4,046,889%2526RS%3DPN%2F4,046,889&PageNum=&Rtype=&SectionNum=&idkey=4F20FB6466C1 |date=2019-05-18 }}
			* drugdesign.org
	*
	*
	{{ACE inhibitors}}		{{ACE inhibitors}}
			{{Angiotensin receptor modulators}}
			{{Leukotriene signaling modulators}}
			{{Portal bar | Medicine}}
			{{Authority control}}
	]		]
			]
			]
	]		]
			]
	]		]
	]		]
	]		]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]