Moexipril hydrochloride

Description

Moexipril hydrochloride is a novel ACE inhibitor first marketed in the U.S.A. for the treatment of hypertension as a monotherapy and as a second-line therapy in combination with diuretics or calcium antagonists. Like other ACE inhibitors, moexipril is a prodrug that is converted in the liver to its diacid moexiprilat which is the active agent. Moexipril displays a higher in vitro inhibitory potency to ACE than enalapril although its effectiveness in reduction of blood pressure in hypertensive patients is similar to that seen with enalapril. It is orally active with a rapid onset and prolonged duration of action. Excellent tolerability has been reported. Moexipril is distinguished by its lower cost than other marketed ACE inhibitors.

Chemical Properties

Crystalline Solid

Originator

Warner-Lambert (U.S.A.)

Uses

Moexipril HCl is a potent orally active non-sulfhydryl angiotensin converting enzyme inhibitor (ACE) with IC50 of 0.041 μM, which is used for the treatment of hypertension and congestive heart failure

Uses

Angiotensin converting enzyme (ACE) inhibitor; dimethoxy analog of quinapril

Definition

ChEBI: Moexipril hydrochloride is a dipeptide.

Manufacturing Process

1) A solution of 2.0 g of t-butyl alanine (S-form) and 3.78 g of ethyl 2-bromo- 4-phenylbutanoate in 25 ml of DMF was treated with 1.8 ml of triethylamine and the solution was heated at 70°C for 18 hours. The solvent was removed at reduced pressure and the residue was mixed with water and extracted with ethyl ether. The organic layer was washed with water and dried over magnesium sulfate. Concentration of the solvent at reduced pressure gave the oily ethyl-α-[(1-carboxyethyl)amino]benzene-t-butanoate.
A solution of 143.7 g of this t-butyl ester in 630 ml of trifluoroacetic acid was stirred at room temperature for one hour. The solvent was removed at reduced pressure and the residue was dissolved in ethyl ether and again evaporated. This operation was repeated. Then the ether solution was treated dropwise with a solution of hydrogen chloride gas in ethyl ether until precipitation ceased. The solid, collected by filtration, was a mixture of diastereoisomers of ethyl-α-[(1-carboxyethyl)amino]benzenebutanoate hydrochloride, melting point 153-165°C; [α]D23 = +3.6° (1% MeOH).
The free amino acid (S,S-form) was prepared by treatment of an aqueous solution of the hydrochloride with saturated sodium acetate. The product was filtered, washed efficiently with cold water and recrystallized from ethyl acetate; melting point 149-151°C; [α]D23 = +29.7°.
2) A stirred solution of 0.0158 mole of ethyl-α-[(1-carboxyethyl)amino] benzenebutanoate hydrochloride in 200 ml of methylene chloride was treated successively with 1.60 g (0.0158 mole) of triethylamine, 0.0158 mole of 1- hydroxybenzotriazole, 0.0158 mole of 1,2,3,4-tetrahydro-6,7-dimethoxy-3- isoquinolinecarboxylic acid and then with 0.0158 mole of dicyclohexylcarbodiimide in 10 ml of methylene dichloride. Dicyclohexylurea gradually separated. The mixture was allowed to stand at room temperature overnight. Hexane (300 ml) was added and the urea was filtered. The filtrate was washed with 250 ml of saturated sodium bicarbonate, dried over sodium sulfate and concentrated to remove solvent. The viscous residue was triturated with 50 ml of ether and filtered to remove insolubles. The filtrate was concentrated to give 2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1- oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid.
After addition of hydrochloric acid was obtained 2-[2-[[1-(ethoxycarbonyl)-3- phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3- isoquinolinecarboxylic acid, hydrochloride.

brand name

Univasc (Schwarz Pharma).

Therapeutic Function

Antihypertensive

Hazard

Moderately toxic by ingestion.

Biological Activity

Angiotensin-converting enzyme (ACE) inhibitor that is hydrolyzed in the liver to the active metabolite moexiprilat (IC 50 values are 2.1 and 2700 nM for moexiprilat and moexipril respectively). Antihypertensive; decreases mean blood pressure in the spontaneous hypertensive rat (SHR). Also blocks degradation of bradykinin into inactive metabolites.

Clinical Use

Angiotensin-converting enzyme inhibitor:
Hypertension

Drug interactions

Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: antagonism of hypotensive effect and increased risk of renal impairment with NSAIDs; hyperkalaemia with ketorolac and other NSAIDs.
Antihypertensives: increased risk of hyperkalaemia, hypotension and renal failure with ARB’S and aliskiren.
Bee venom extract: possible severe anaphylactoid
reactions when used together. Ciclosporin: increased risk of hyperkalaemia and nephrotoxicity.
Cytotoxics: increased risk of angioedema with everolimus.
Diuretics: enhanced hypotensive effect; hyperkalaemia with potassium-sparing diuretics.
ESAs: increased risk of hyperkalaemia; antagonism of hypotensive effect.
Gold: flushing and hypotension with sodium aurothiomalate.
Lithium: reduced excretion (possibility of enhanced lithium toxicity).
Potassium salts: increased risk of hyperkalaemia.
Tacrolimus: increased risk of hyperkalaemia and nephrotoxicity.

Metabolism

Moexipril is a prodrug that is converted to an active metabolite, moexiprilat in the gastrointestinal mucosa and liver. Moexipril is excreted mainly in the urine as moexiprilat, unchanged drug, and other metabolites; some moexiprilat may also be excreted in the faeces.