Каптоприл

Описание

Captopril is the most studied of the angiotensin-converting enzyme inhibitors proposed as an antihypertensive drug. It blocks angiotensin-converting enzyme, which suppresses formation of angiotensin II and relieves its vasoconstricting effect on arterial and venous vessels. Overall vascular peripheral tension is reduced, which results in the lowering of arterial pressure.

Химические свойства

White or almost white, crystalline powder.

Использование

Captopril has also been shown to inhibit the formation of angiotensin II, a bioactive peptide that stimulates angiogenesis and increases microvessel density. Captopril demonstrates noncompetitive inhibition of tyrosinase monophenolase activity and competitive inhibition of diphenolase activity

Определение

ChEBI: A L-proline derivative in which L-proline is substituted on nitrogen with a (2S)-2-methyl-3-sulfanylpropanoyl group. It is used as an anti-hypertensive ACE inhibitor drug.

Биологические функции

Captopril (Capoten) is an orally effective ACE inhibitor with a sulfhydryl moiety that is used in binding to the active site of the enzyme. Captopril blocks the blood pressure responses caused by the administration of angiotensin I and decreases plasma and tissue levels of angiotensin II.

Общее описание

Captopril, 1-[(2S)-3-mercapto-2-methyl-1-oxopropionyl]proline (Capoten), blocks the conversion of angiotensinI to angiotensin II by inhibiting the convertingenzyme. The rational development of captopril as an inhibitorof ACE was based on the hypothesis that ACE and carboxypeptidaseA functioned by similar mechanisms. It wasnoted that d-2-benzylsuccinic acid was a potent inhibitor ofcarboxypeptidase A, but not ACE. By use of this small molecule as a prototype, captopril was designed with a carboxylgroup on a proline and a thiol group was introduced toenhance the binding to the zinc ion of ACE. The importantbinding points at the active site of ACE are thought to be anarginine residue, which provides a cationic site that attracts acarboxylate ion, and a zinc ion, which can polarize a carbonylgroup of an amide function to make it more susceptible to hydrolysis.Hydrophobic pockets lie between these groups in theactive site, as does a functional group that forms a hydrogenbond with an amide carbonyl.

Побочные эффекты

Approximately 10% of the patients treated with captopril report a dose-related maculopapular rash that often disappears when the dosage of captopril is reduced. Other common adverse effects are fever, a persistent dry cough (incidence as high as 39%), initial dose hypotension, and a loss of taste that may result in anorexia. These effects are reversed when drug therapy is discontinued. More serious toxicities include a 1% incidence of proteinuria and glomerulonephritis; less common are leukopenia and agranulocytosis. Since food reduces the bioavailability of captopril by 30 to 40%, administration of the drug an hour before meals is recommended. All converting enzyme inhibitors are contraindicated in patients with bilateral renal artery disease or with unilateral renal artery disease and one kidney. Use under these circumstances may result in renal failure or paradoxical malignant hypertension.

Метаболизм

The onset of action following oral administration of captopril is about 15 minutes, with peak blood levels achieved in 30 to 60 minutes. Its apparent biological half-life is approximately 2 hours, with its antihypertensive effects observed for 6 to 10 hours. The kidneys appear to play a major role in the inactivation of captopril.

Методы очистки

Purify it by recrystallisation from EtOAc/hexane. It is also purified by dissolving in EtOAc and chromatographed on a column of Wakogel C200 using a linear gradient of MeOH in EtOAc (0-100o) and fractions which give a positive nitroprusside test (for SH), are combined, evaporated and recrystallised from EtOAc/hexane (1:1), to give white crystals with [] D -128.2o (c 2.0, EtOH). [Nam J Pharm Sci 73 1843 1984]. Alternatively, dissolve it in H2O, apply to a column of AG-50Wx2 (BioRad) and elute with H2O. The free acid is converted to the dicyclohexylamine salt in MeCN by addition of the amine until the pH is 8-9. The salt is converted to the free acid by shaking with EtOAc and 10% aqueous KHSO4 or passage through an AG50Wx2 column. The EtOAc solution is dried (MgSO4), evaporated to dryness and the residue is recrystallised as above from EtOAc/hexane [Cushman et al. Biochemistry 16 5484 1977, NMR and IR: Horii & Watanabe Yakugaku Zasshi (J Pharm Soc Japan) 81 1786 1961]. It is an antihypertensive because it is a potent competitive inhibitor of the angiotensive convertive enzyme (ACE-inhibitor) with a Ki value of 0.0017\M [Shimazaki et al. Chem Pharm Bull Jpn 30 3139 1982].