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a drug (trade name Capoten) that blocks the formation of angiotensin in the kidneys resulting in vasodilation; used in the treatment of hypertension and congestive heart failure (同)Capoten

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/11 23:22:19」(JST)

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Captopril (rINN) /ˈkæptəprɪl/ is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. 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 was discovered and developed at Squibb and Sons Pharmaceuticals based on concepts pioneered by Nobel Laureate John Vane and is now marketed by Bristol-Myers Squibb under the trade name Capoten.^[1]

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

Clinical use

Captopril's main uses are based on its vasodilation and inhibition of some renal function activities. These benefits are most clearly seen in: 1) Hypertension 2) Cardiac conditions such as congestive heart failure and after myocardial infarction 3) Preservation of kidney function in diabetic nephropathy

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.^[3]

It has also been investigated for use in the treatment of cancer.^[4]

History

Captopril was developed in 1975 by three researchers at the U.S. drug company Squibb (now Bristol-Myers Squibb): 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.

The development of captopril was among the earliest successes of the revolutionary concept of ligand-based drug design. The renin-angiontensin-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 were renin and 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^[5]^[6]^[7] 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^[8] 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,^[9] 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.

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.

The development of captopril has been claimed as an instance of 'biopiracy' (commercialization of traditional medicines), since no benefits have flowed back to the indigenous Brazilian tribe who first used pit viper venom as an arrowhead poison.^[10]

Captopril synthesis of Shimazaki, Watanabe, et al.

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.^[11]

Pharmacokinetics

Unlike the majority of ACE inhibitors, captopril is not administered as a prodrug (the only other being lisinopril).^[12] 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 in urine.^[13]

Developments from captopril

Limitations of captopril

The adverse drug reaction (ADR) profile of captopril is similar to other ACE inhibitors, with cough being the most common ADR.^[14] However, captopril is also commonly associated with rash and taste disturbances (metallic or loss of taste), which are attributed to the unique thiol moiety.^[15]

Captopril also has a relatively poor pharmacokinetic profile. The short half-life necessitates two or three times per day dosing, which may reduce patient compliance.

Subsequent ACE inhibitors

The adverse effect and pharmacokinetic limitations of captopril stimulated the development of enalapril and subsequent ACE inhibitors. These were specifically designed to lack the sulfhydryl moiety believed to be responsible for rash and taste disturbance.^[16] Most subsequent ACE inhibitors are given as prodrugs, to improve oral bioavailability. All have longer half-lives and are given once or twice daily, which may improve patient compliance.

Adverse effects

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, and leukopenia.^[17] 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. Hyperkalemia can occur, especially if used with other drugs which elevate potassium level in blood, such as potassium-sparing diuretics. Other side effects are:

Itching
Headache
Tachycardia
Chest pain
Palpitations
Weakness

Overdose

Captopril (as other ACE inhibitors) overdose can be antagonized with naloxone.^[18]^[19]^[20]

References

^ Bryan, Jenny (2009). "From snake venom to ACE inhibitor the discovery and rise of captopril". Pharmaceutical Journal. Retrieved 2015-01-08.
^ Akif, M.; Georgiadis, D.; Mahajan, A.; Dive, V.; Sturrock, E. D.; Isaac, R. E.; Acharya, K. R. (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. PMID 20488190. edit
^ Novel Pharmacological Approaches to the Treatment of Depression
^ Attoub S; Gaben AM; Al-Salam S et al. (September 2008). "Captopril as a potential inhibitor of lung tumor growth and metastasis". Ann. N. Y. Acad. Sci. 1138: 65–72. doi:10.1196/annals.1414.011. PMID 18837885.
^ Ng KKF and Vane JR: Conversion of angiotensin I to angiotensin II. Nature 1967, 216, 762-766.
^ Ng KKF and Vane JR: Fate of angiotensin I in the circulation. Nature, 1968, 218, 144-150.
^ Ng KKF and Vane JR: Some properties of angiotensin converting enzyme in the lung in vivo. Nature, 1970, 225, 1142-1144.
^ 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.
^ Smith CG, Vane JR (May 2003). "The discovery of captopril". FASEB J. 17 (8): 788–9. doi:10.1096/fj.03-0093life. PMID 12724335.
^ Ellsworth B., Brazil to step up crackdown on "biopiracy" in 2011, Ruters, Dec. 22, 2010
^ Shimazaki, M.; Hasegawa, J.; Kan, K.; Nomura, K.; Nose, Y.; Kondo, H.; Ohashi, T.; Watanabe, K. (1982). "Synthesis of captopril starting from an optically active .BETA.-hydroxy acid". Chem. Pharm. Bull. 30 (9): 3139–3146. doi:10.1248/cpb.30.3139.
^ Brown, NJ; Vaughan, DE (1998). "Angiotensin-converting enzyme inhibitors". Circulation 97 (14): 1411–20. doi:10.1161/01.cir.97.14.1411. PMID 9577953.
^ Duchin, KL; McKinstry, DN; Cohen, AI; Migdalof, BH (1988). "Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases". Clinical pharmacokinetics 14 (4): 241–59. doi:10.2165/00003088-198814040-00002. PMID 3292102.
^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
^ Atkinson, AB; Robertson, JI (1979). "Captopril in the treatment of clinical hypertension and cardiac failure". Lancet 2 (8147): 836–9. doi:10.1016/S0140-6736(79)92186-X. PMID 90928.
^ Patchett, AA; Harris, E; Tristram, EW; Wyvratt, MJ; Wu, MT; Taub, D; Peterson, ER; Ikeler, TJ; Ten Broeke, J; Payne, L. G.; Ondeyka, D. L.; Thorsett, E. D.; Greenlee, W. J.; Lohr, N. S.; Hoffsommer, R. D.; Joshua, H.; Ruyle, W. V.; Rothrock, J. W.; Aster, S. D.; Maycock, A. L.; Robinson, F. M.; Hirschmann, R.; Sweet, C. S.; Ulm, E. H.; Gross, D. M.; Vassil, T. C.; Stone, C. A. (1980). "A new class of angiotensin-converting enzyme inhibitors". Nature 288 (5788): 280–3. doi:10.1038/288280a0. PMID 6253826.
^ "Captopril (ACE inhibitor): side effects". lifehugger. 07-09-2008. Retrieved 2009-05-02. Check date values in: |date= (help)
^ Goldfrank's toxicologic emergencies, Lewis R. Goldfrank,Neal Flomenbaum, page 953.
^ Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs, Jeffrey K. Aronson, page 120.
^ Ajayi, A A (1985). "Effect of naloxone on the actions of captopril". Clin Pharmacol Ther 38 (5): 560-565.

External links

U.S. Patent 4,046,889
RxList monograph: Capoten
U.S. National Library of Medicine: Drug Information Portal - Captopril

UpToDate Contents

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2. 駆出率低下を伴う心不全におけるACE阻害剤：治療使用 ace inhibitors in heart failure with reduced ejection fraction therapeutic use
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English Journal

Antihypertensive nano-ceuticales based on chitosan biopolymer: Physico-chemical evaluation and release kinetics.

Niaz T1, Shabbir S2, Manzoor S3, Rehman A4, Rahman A5, Nasir H6, Imran M7.
Carbohydrate polymers.Carbohydr Polym.2016 May 20;142:268-74. doi: 10.1016/j.carbpol.2016.01.047. Epub 2016 Jan 25.
Prime risk factor behind cardiovascular associated mortality and morbidity is hypertension. The main challenge with antihypertensive (AHT) drug therapy is their extreme hydrophobic nature and very low oral bio-availability; which result into higher dosage/frequency and associated side effects of dru
PMID 26917399

Reusable fluorescent sensor for captopril based on energy transfer from photoluminescent graphene oxide self-assembly multilayers to silver nanoparticles.

Sun X1, Liu B2, Li S2, Li F2.
Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.Spectrochim Acta A Mol Biomol Spectrosc.2016 May 15;161:33-8. doi: 10.1016/j.saa.2016.02.018. Epub 2016 Feb 24.
In this work we designed a self-assembly multilayers, in which photoluminescent graphene oxide was employed as a fluorescence probe. This multilayers film can effectively recognize captopril by resonance energy transfer from graphite oxide to silver nanoparticles. A new interfacial sensing method fo
PMID 26945122

Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism.

Umakoshi H1, Naruse M2, Wada N1, Ichijo T1, Kamemura K1, Matsuda Y1, Fujii Y1, Kai T1, Fukuoka T1, Sakamoto R1, Ogo A1, Suzuki T1, Nanba K1, Tsuiki M1; WAVES-J Study Group.
Hypertension.Hypertension.2016 May;67(5):1014-9. doi: 10.1161/HYPERTENSIONAHA.115.06607. Epub 2016 Mar 14.
Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to in
PMID 26975712

Japanese Journal

Involvement of Renin-Angiotensin System in Damage of Angiotensin-Converting Enzyme Inhibitor Captopril on Bone of Normal Mice

Liu Jin-Xin,Wang Liang,Zhang Yan
Biological & pharmaceutical bulletin 38(6), 869-875, 2015-06
NAID 40020471384

Involvement of Renin–Angiotensin System in Damage of Angiotensin-Converting Enzyme Inhibitor Captopril on Bone of Normal Mice

, ,
Biological and Pharmaceutical Bulletin 38(6), 869-875, 2015
… This study was performed to investigate the effect of angiotensin-converting enzyme inhibitor, captopril, on bone metabolism and histology, and the action of captopril on the components of the skeletal renin–angiotensin system (RAS) and bradykinin receptor in normal male mice. … The mice were orally administered captopril (10 mg/kg) for 4 weeks with vehicle-treated mice as normal control. …
NAID 130005072666

Losartan and Sodium Nitroprusside Effectively Protect against Renal Impairments after Ischemia and Reperfusion in Rats

, , [他],
Biological and Pharmaceutical Bulletin 38(5), 753-762, 2015
… Different degrees of preventive effects were observed in rats treated with captopril, BQ-123 (endothelin type A receptor antagonist), sodium nitroprusside (SNP, a nitric oxide donor), and losartan (angiotensin II type 1 receptor antagonist). … Only minimal changes in renal morphology were observed after treatment with losartan, SNP, captopril, and BQ-123 compared with control animals. …
NAID 130005068102

Related Pictures

★リンクテーブル★

リンク元	「アンジオテンシン変換酵素阻害薬」「膜性腎症」「薬理学」
拡張検索	「captopril renography」

「アンジオテンシン変換酵素阻害薬」

Captopril
Systematic (IUPAC) name
	(2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]; pyrrolidine-2-carboxylic acid
Clinical data
Trade names	Capoten
AHFS/Drugs.com	monograph
MedlinePlus	a682823
Pregnancy; category	AU: D; US: D (Evidence of risk);
Legal status	℞ (Prescription only);
Routes of; administration	oral
Pharmacokinetic data
Bioavailability	70–75%
Metabolism	hepatic
Biological half-life	1.9 hours
Excretion	renal
Identifiers
CAS Registry Number	62571-86-2
ATC code	C09AA01
PubChem	CID: 44093
IUPHAR/BPS	5158
DrugBank	DB01197
ChemSpider	40130
UNII	9G64RSX1XD
KEGG	D00251
ChEBI	CHEBI:3380
ChEMBL	CHEMBL1560
PDB ligand ID	X8Z (PDBe, RCSB PDB)
Chemical data
Formula	C9H15NO3S
Molecular mass	217.29
	SMILES O=C(O)[C@H]1N(C(=O)[C@H](C)CS)CCC1 ;
	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 ; Key:FAKRSMQSSFJEIM-RQJHMYQMSA-N ;
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　　[★]

英: angiotensin-converting enzyme inhibitor angiotensin converting enzyme inhibitor , ACE inhibitor, ACEI
同: アンジオテンシン変換酵素阻害剤アンギオテンシン変換酵素阻害薬アンギオテンシン変換酵素阻害剤アンジオテンシン転換酵素阻害薬、ACE阻害薬 ACE阻害剤 ACE inhibitor、アンギオテンシン変換酵素拮抗薬, アンギオテンシン変換酵素拮抗薬, angiotensin-converting enzyme antagonist
関: アンジオテンシン, アンジオテンシン転換酵素 ACE, 1型アンジオテンシンII受容体拮抗薬アンジオテンシンII受容体拮抗薬 ARB