Enalaprilat

Structural formula
Structural formula of the ( S , S , S ) -diastereomer (all- S -diastereomer)
General
Non-proprietary name	Enalaprilat
other names	(2 S ) -1 - [(2 S ) -2 - {[(1 S ) -1-carboxy-3-phenylpropyl] amino} propanoyl] pyrrolidine-2-carboxylic acid ( IUPAC ) 1- { N -1 ( S ) -Carboxy-3-phenylpropyl} - L -alanyl- L -proline ( WHO ) Enalaprilic acid Enalapril diacid ( S ) -1 - [( S ) -2 - (( S ) -1-ethoxycarbonyl-3-phenylpropylamino) propionyl] pyrrolidine-2-carboxylic acid ( IUPAC )
Molecular formula	C 18 H 24 N 2 O 5
External identifiers / databases
CAS number 76420-72-9 (enalaprilat) 84680-54-6 (dihydrate) EC number 278-459-3 ECHA InfoCard 100.071.306 PubChem 5462501 ChemSpider 4575429 DrugBank DB09477 Wikidata Q5375179
properties
Molar mass	348.4 g mol −1 (enalaprilat) 384.43 g mol −1 (dihydrate)
Physical state	firmly
Melting point	148–151 ° C (dihydrate)
solubility	poorly to very poorly soluble in water, slightly soluble in methanol, practically insoluble in acetonitrile (dihydrate)
safety instructions
GHS labeling of hazardous substances Dihydrate no GHS pictograms H and P phrases H: no H-phrases P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Enalaprilat is a synthetic dipeptide and, as an active pharmaceutical ingredient, belongs to the class of ACE inhibitors . It was the first representative with two carboxylic acid groups. It is formed in the liver by enzymatic hydrolysis of enalapril and is the actual active ingredient. The compound contains the chiral amino acids L- alanine and L- proline as structural elements and is therefore chiral itself. The latter amino acid had already been used in the ACE inhibitor captopril . The compound is a colorless solid.

history

The dicarboxylic acid was first synthesized in a research program by the US company Merck Sharp & Dome to synthesize new inhibitors of the angiotensin converting enzyme (ACE) with the aim of finding new antihypertensive agents. It carried the internal name MK-422.

synthesis

For the first pharmacological investigations, the dicarboxylic acid was obtained by reductive condensation of 2-oxo-4-phenylbutyric acid with the amino group of the dipeptide L- alanyl- L- proline. Here, a first carried addition of the NH ₂ group to the keto group and, after addition of the reducing agent sodium cyanoborohydride (NaCNBH ₃ ) in situ a hydrogenation of the chemical equilibrium stationary imine .

Since the keto group and the imime are prochiral structural elements, two diastereomers with ( S, S, S ) or ( R, S, S ) configuration arise a priori , which were separated by chromatography .

Pharmacological properties

The inhibiting effect of the synthesized substances on the isolated angiotensin-activating enzyme (ACE) was investigated in vitro . It was found that the ( R, S, S ) -diastereomer had a weaker effect than the ( all-S ) -configured molecule; because the mean inhibitory concentrations IC50 differ by almost two powers of ten (8.2 × 10 ⁻⁷ versus 1.2 × 10 ⁻⁹ mol). The substance, which is around 700 times more active, is already effective in the nanomolar range.

use

( all-S ) -Enalaprilat shows deficiencies in direct use as a medicinal substance for humans. It can only be administered intravenously. The enalaprilat dihydrate is used here. In the gastrointestinal tract enalaprilat is absorbed not enough and therefore can not be orally administered in tablet form. For this reason, prodrugs were synthesized which only release the active ingredient in vivo , e.g. B. Enalapril .

Trade names

• EnaHEXAL iv (D), Vasotec iv ( CA )

Individual evidence

1. ^ W. Forth, D. Henschler, W. Rummel: General and special pharmacology and toxicology , 5th edition, page 158, Bibliographisches Institut and FA Brockhaus, Mannheim-Vienna-Zurich (1987). ISBN 3-411-03150-6
2. ^ The Merck Index, 11th Edition (1989), page 558, entry no.3522.
3. ↑ Ph. Eur. 8th edition, basic work 2014.
4. ↑ ^{a b} Data sheet Enalaprilat dihydrate, ≥98% (HPLC) from Sigma-Aldrich , accessed on September 7, 2019 ( PDF ).
5. ^ The Merck Index, 11th Edition (1989), page 558, entry no.3522.
6. ↑ External identifiers or database links for enalaprilat dihydrate : CAS number: 84680-54-6, EC number: 689-724-1 , ECHA InfoCard: 100.216.639 , PubChem : 6917719 , ChemSpider : 5292946 , DrugBank : DB00584 , Wikidata : Q27126932 .
7. ↑ Quoted and freely translated from the English WP, Lemma: Enalaprilat.