Enalapril

Structural formula
General
Non-proprietary name	Enalapril
other names	1- { N - [( S ) -1-ethoxycarbonyl-3-phenylpropyl] - ( S ) -alanyl} - ( S ) -proline; (all- S ) -1- [ N - (1-ethoxycarbonyl-3-phenylpropyl) -alanyl] -proline;
Molecular formula	C 20 H 28 N 2 O 5
Brief description	white solid (maleate)
External identifiers / databases
EC number	616-271-9
ECHA InfoCard	100.119.661
PubChem	5388962
ChemSpider	4534998
DrugBank	DB00584
Wikidata	Q422185
Drug information
ATC code	C09 AA02
Drug class	Antihypertensive drugs
Mechanism of action	ACE inhibitors
properties
Molar mass	376.45 g mol −1
Physical state	firmly
Melting point	143-144.5 ° C (enalapril maleate)
solubility	soluble in water: 25 g · l −1
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances Maleate	no GHS pictograms
	no GHS pictograms
H and P phrases	H: no H-phrases
	P: no P-phrases
Toxicological data	2973 mg kg −1 ( LD 50 , rat , oral )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Enalapril is a drug from the group of ACE inhibitors that is used to treat arterial hypertension (high blood pressure) and heart failure . Enalapril itself is an inactive prodrug . After activation by hydrolytic cleavage of ethanol to form enalaprilat, its active principle is based on the inhibition of the angiotensin converting enzyme (ACE).

chemistry

Enalapril is based on the ACE-inhibiting peptides of the venom of the Jararaca lance viper (Bothrops jararaca), a Brazilian snake species . Enalapril contains a stabilized dipeptide structure and is a condensation product of the amino acids ( S ) - proline and ( S ) - alanine and of 2-oxo-4-phenylbutyric acid ethyl ester.

In the research laboratories of the US company Merck Sharp & Dome (MSD), over 200 variants of the general formula ( Markush formula ) (I) were produced in a program for the synthesis of new inhibitors of the angiotensin converting enzyme (ACE) .

In contrast to the precursor captopril , these do not contain a sulfur atom. These included some compounds which, in tests, showed high activity to inhibit ACE. The international non-proprietary name Enalapril was awarded for the active ingredient. The company's internal name for the connection was MK-421. The MSD researchers' results were published in the November 1980 journal Nature . Enalapril contains the amino acids alanine and at the end proline as structural parts . This amino acid was used in the first synthetic ACE inhibitor, captopril . Enalapril was the second inhibitor whose properties have also been studied particularly thoroughly. Enalapril contains three stereocenters , which means that the active ingredient represents only one diastereomer of the possible eight different stereoisomers . Only the stereochemically uniform (all- S ) isomer is used as a medicinal substance .

synthesis

For the first pharmacological investigations, the compound was obtained by reductive condensation of ethyl 2-oxo-4-phenylbutyrate with the amino group of the dipeptide L-alanyl-L-proline [synonym: ( S ) -alanyl- ( S ) -proline]. In this case, the NH ₂ group of the dipeptide first reacts with the keto group of the reactant with elimination of water . After addition of a reducing agent (in this case , sodium cyanoborohydride , NaCNBH ₃ ) in situ a hydrogenation of the imine .

Since the keto group and the imime are prochiral structural elements, two diastereomers with ( S, S, S ) and ( R, S, S ) configuration are formed in this synthesis , which were separated by chromatography . For further syntheses see.

pharmacology

Enalapril is an inactive prodrug , which was achieved by esterifying the free carboxylic acid function with ethanol . This ethanol group is split off in the organism in the liver by esterases , creating the active, so-called enalaprilat . It should be better known as 'enalaprilic acid' or 'enalapril diacid' because it is a dicarboxylic acid or its anion.

application areas

Enalapril is used individually (monotherapy) and in combination with other antihypertensive agents (combination therapy, especially with diuretics or calcium channel blockers) mainly for the treatment of high blood pressure. It is also considered the first choice for the treatment of heart failure. In contrast to some other ACE inhibitors, such as B. Ramipril , Enalapril has not shown any effectiveness in the prophylaxis (prevention) of myocardial infarction .

Mechanism of action

Enalapril leads as inhibitor of angiotensin converting enzyme in a decreased formation of angiotensin II from angiotensin I . This reduced formation of angiotensin II causes a decrease in the tone of the blood vessels and thus a decrease in blood pressure. The decrease in the angiotensin II level also leads to a reduction in the release of aldosterone from the adrenal cortex and thus to an influence on the water balance (see also renin-angiotensin-aldosterone system ).

Side effects

Most of the side effects of enalapril are associated with slower breakdown and accumulation of bradykinin due to ACE inhibitors . These include skin reactions such as B. exanthema and hives , also angioedema . Serious allergic skin reactions, however, are only very rarely observed.

Respiratory side effects include dry cough, hoarseness, and sore throat. Asthma attacks and shortness of breath can also occur, albeit rarely.

As a result of the main action of enalapril, there may be an excessive decrease in blood pressure. As a result, dizziness, headache, and drowsiness may occasionally be observed. Serious cardiovascular events such as angina pectoris , myocardial infarction and syncope have only been reported in isolated cases.

As a result of the interference with the water and electrolyte balance, kidney dysfunction can occasionally be observed. A proteinuria (excretion of protein in the urine) is, however, rarely observed.

Since enalapril in pregnancy u. a. Can cause growth and bone formation disorders in the child combined with increased mortality, enalapril must not be taken during this time and should be replaced by other suitable therapeutic measures.

Interactions

Enalapril enhances the blood sugar lowering effect of insulin and oral antidiabetic drugs as well as the blood count-altering effects of immunosuppressants.

By interfering with the water and electrolyte balance, the excretion of electrolytes can be slowed down, which should be observed in particular when treating with lithium and potassium-sparing diuretics.

When combined with other antihypertensive drugs, increased blood pressure lowering should be taken into account.

literature

Hager's Encyclopedia of Medicinal Substances and Drugs, Wolfgang Blaschek et al. (Ed.), 6th edition (2007), Vol. 6, pages 602-605. Stuttgart [u. a.]: Wiss. Verlagsges. [u. a.] ISBN 978-3-8047-2384-9 .

Trade names

Monopreparations

ACEpril (CH), Alapril (A), Elpradil (CH), Epril (CH), Mepril (A), Pres, Renistad (A), Renitec (A), Reniten (CH), Xanef (D), numerous generics ( TOP, ROOF)

Veterinary medicine: Enacard, Enadog, Enalatab, Prilenal

Combination preparations

In combination with hydrochlorothiazide : Co-Acepril (CH), Co-Renitec (A), Co-Mepril (A), Co-Renistad (A), Coenytyrol (A), Elpradil HCT (CH), Epril plus (CH), Renitec plus (A), Reniten plus (CH), generics (D, A, CH)
In combination with lercanidipine : Carmen ACE (D), Zaneril (D), Zanipress (D), Zanipril (A)
In combination with nitrendipine : Baroprine (A), Cenipress (A), Eneas (D)

Individual evidence

↑ ^a ^b ^c ^d data sheet Enalapril from Sigma-Aldrich , accessed on December 8, 2016 ( PDF ).
↑ ^a ^b The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals . 14th edition, 2006, p. 607, ISBN 978-0-911910-00-1 .
^ Axel Kleemann , Jürgen Engel, Bernd Kutscher and Dietmar Reichert: Pharmaceutical Substances, 4th edition (2000), Thieme-Verlag Stuttgart, pp. 739-741, ISBN 978-1-58890-031-9 .
↑ European patent application 12 401.
^ EE Harris et al. U.S. Patent 4,374,829 (1980, 1983) both to MSD
^ AA Patchett et al .: A new class of angiotensin-converting enzyme inhibitors. Nature 288: 280-283 (1980).
↑ D. Heber, J. Mann in Hagers Encyclopedia (see literature).
^ Axel Kleemann Jürgen Engel, Bernhard Kutscher and Dietmar Reichert: Pharmaceutical Substances, 5th edition (2009), Thieme-Verlag Stuttgart-New York, pp. 469-471, ISBN 978-1-58890-031-9 .
↑ W. Forth, D. Henschler, W. Rummel: General and special pharmacology and toxicology. 5th edition, page 158, Bibliographisches Institut and FA Brockhaus AG, Mannheim, Vienna, Zurich, 1987, ISBN 3-411-03150-6 .
↑ Rote Liste Service GmbH (Ed.): Rote Liste 2017 - drug directory for Germany (including EU approvals and certain medical devices) , Rote Liste Service GmbH, Frankfurt / Main, 2017, edition 57, ISBN 978-3-946057-10 -9 , p. 553.

[Sigma-1] ta sheet Enalapril from Sigma-Aldrich , accessed on December 8, 2016 ( PDF ).

[Merck-2] The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals . 14th edition, 2006, p. 607, ISBN 978-0-911910-00-1 .

[A._Kleemann-3] Axel Kleemann , Jürgen Engel, Bernd Kutscher and Dietmar Reichert: Pharmaceutical Substances, 4th edition (2000), Thieme-Verlag Stuttgart, pp. 739-741, ISBN 978-1-58890-031-9 .

[4] European patent application 12 401.

[5] EE Harris et al. U.S. Patent 4,374,829 (1980, 1983) both to MSD

[6] AA Patchett et al .: A new class of angiotensin-converting enzyme inhibitors. Nature 288: 280-283 (1980).

[7] D. Heber, J. Mann in Hagers Encyclopedia (see literature).

[8] Axel Kleemann Jürgen Engel, Bernhard Kutscher and Dietmar Reichert: Pharmaceutical Substances, 5th edition (2009), Thieme-Verlag Stuttgart-New York, pp. 469-471, ISBN 978-1-58890-031-9 .

[9] W. Forth, D. Henschler, W. Rummel: General and special pharmacology and toxicology. 5th edition, page 158, Bibliographisches Institut and FA Brockhaus AG, Mannheim, Vienna, Zurich, 1987, ISBN 3-411-03150-6 .

[Rote_Liste-10] Rote Liste Service GmbH (Ed.): Rote Liste 2017 - drug directory for Germany (including EU approvals and certain medical devices) , Rote Liste Service GmbH, Frankfurt / Main, 2017, edition 57, ISBN 978-3-946057-10 -9 , p. 553.