Alacepril

Alacepril is a thioacetate ester and a dipeptide. It has a role as an EC 3.4.15.1 (peptidyl-dipeptidase A) inhibitor.|Alacepril is a long-acting, sulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor with antihypertensive activity. As a prodrug, alacepril is rapidly metabolized to captopril; captopril competitively binds to and inhibits ACE, thereby blocking the conversion of angiotensin I to angiotensin II. This prevents the potent vasoconstrictive actions of angiotensin II and results in vasodilation. Captopril also decreases angiotensin II-induced aldosterone secretion by the adrenal cortex, which leads to an increase in sodium excretion and subsequently increases water outflow.

1-(D-3-Acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine 1-(D-3-Acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine tert-butyl ester (2.5 g) was dissolved in a mixture of anisole (18 ml) and trifluoroacetic acid (37 ml). The solution was allowed to stand at room temperature for one hour and then concentrated to dryness under reduced pressure. The residue was crystallized from diethyl ether. Crystals collected were recrystallized from ethanol/n-hexane to give the title compound (1.8 g), m.p. 155-156 C. [alpha]D25 =-81.3 (c=1.02, ethanol) IR numaxKBr cm-1: 3240, 1740, 1685, 1645, 1620.EXAMPLE 27 1-(D-3-Acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine To a solution of L-prolyl-L-phenylalanine (0.52 g) in 1 N sodium hydroxide (2 ml) cooled in an ice bath, 3-acetylthio-2-methylpropanoyl chloride (0.36 g) and 2 N sodium hydroxide (1 ml) were added with vigorous stirring. After 3 hours' stirring at room temperature, the solution was washed with diethyl ether, acidified, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was treated as in the third paragraph of Example 26 to give the title compound.EXAMPLE 23 1-(D-3-Mercapto-2-methylpropanoyl)-L-prolyl-L-phenylalanine 1-(D-3-Acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine (1.0 g) was suspended in water (20 ml) under argon. The pH of the suspension was maintained at 13 for 1.5 hours using 5 N sodium hydroxide. During this time, the suspension became clear to give a solution. The solution thus obtained was adjusted to pH 2 with concentrated sulfuric acid and extracted with dichloromethane. The organic layer was washed with water, dried and concentrated to give the title compound (0.75 g). The compound thus obtained (0.50 g) was dissolved in 50% ethanol, and calcium hydroxide (48 mg) was added. The solution was concentrated to dryness under reduced pressure. The residue was dissolved in water (50 ml) and the resulting solution was lyophilized to give the calcium salt of the title compound, m.p. 160-180 C. (decomposition). IR numaxKBr cm-1: 3380, 1600, 1410.1-[(2S)-3-(ACETYLTHIO)-2-METHYL-1-OXOPROPYL]-L-PROLYL- L-PHENYLALANINE tert-butyl ester (1.19 g, 0.025 Mol) was dissolved in a solution of trifluoroacetic ACID : CH2CL2 (1: 2, 30 ml) and the reaction was stirred at room temperature for 1 hour. Then it was evaporated under reduced pressure affording 1-[(2S)-3-(ACETYLTHIO)-2-METHYL- 1-OXOPROPYL]-L-PROLYL-L-PHENYLALANINE as a clear oil (1.00 g, 100 %) that was used in the subsequent reaction without any further purification. 1H-NMR (CDC13) : 7.23 (m, 5H), 7.05 (d, 1H), 4.91 (m, 1H), 4.55 (m, 1H), 3.62 (m, 2H), 3.15 (m, 3H), 2.92 (m, 2H), 2.38 (s, 3H), 2.07 (m, 4H), 1.88 (m, 3H), 1.17 (d, 3H).1-[(25)-3-(ACETYLTHIO)-2-METHYL-1-OXOPROPYL]-L-PROLYL- L-phenylalanine (1.00 g, 0.025 Mol), 1-HYDROXY-3- bromomethylbenzene (0.463 g, 0.025 Mol) and 4- DIMETHYLAMINOPYRIDINE (0.060 g, 0.005 Mol) were dissolved in CHC13 (10 ml) and the solution was cooled to 0C. Dicyclohexylcarbodiimide (0.70 g, 0.033 Mol) was then added and the solution was slowly warmed to room temperature and stirred for 5 h. The crude material was concentrated and purified by flash chromatography eluting with EtOAc/n- Hexane 1: 1, affording 1-[(2S)-3-(ACETYLTHIO)-2-METHYL-1- OXOPROPYL]-L-PROLYL-L-PHENYLALANINE 3-bromomethyl phenyl ester (i. e.

Angiotensin-converting enzyme inhibitors are prodrugs that, after oral administration, are converted to deacetylated arapride and captopril. Used for primary and renal hypertension.

Molecular Weight:406.5
XLogP3:2.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:9
Exact Mass:406.15624311
Monoisotopic Mass:406.15624311
Topological Polar Surface Area:129
Heavy Atom Count:28
Complexity:591
Defined Atom Stereocenter Count:3
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes