Moexipril an

angiotensin converting enzyme inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volume ...

(ACE inhibitor) used for the treatment of hypertension and

congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

. Moexipril can be administered alone or with other

antihypertensives Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests that ...

diuretics A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics ...

.Belal, F.F, K.M. Metwaly, and S.M. Amer. "Development of Membrane Electrodes for the Specific Determination of Moexipril Hydrochloride in Dosage Forms and Biological Fluids." Portugaliae Electrochimica Acta. 27.4 (2009): 463-475. It works by inhibiting the conversion of

angiotensin I Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adr ...

angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adr ...

.Rodgers, Katie, Michael C Vinson, and Marvin W Davis. "Breakthroughs: New drug approvals of 1995 -- part 1." Advanstar Communications, Inc. 140.3 (1996): 84. It was patented in 1980 and approved for medical use in 1995. Moexipril is available from Schwarz Pharma under the trade name Univasc.

Side effects

Moexipril is generally well tolerated in elderly patients with hypertension. Hypotension, dizziness, increased cough, diarrhea, flu syndrome, fatigue, and flushing have been found to affect less than 6% of patients who were prescribed moexipril.

Mechanism of action

As an ACE inhibitor, moexipril causes a decrease in ACE. This blocks the conversion of angiotensin I to angiotensin II. Blockage of angiotensin II limits hypertension within the vasculature. Additionally, moexipril has been found to possess cardioprotective properties. Rats given moexipril one week prior to induction of

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ...

, displayed decreased infarct size. The cardioprotective effects of ACE inhibitors are mediated through a combination of angiotensin II inhibition and

bradykinin Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and m ...

proliferation.Hartman, J.C. “The role of bradykinin and nitric oxide in the cardioprotective action of ACE inhibitors.” The Annals of Thoracic Surgery. 60.3 (1995): 789-792. Increased levels of bradykinin stimulate in the production of prostaglandin E₂ and nitric oxide, which cause vasodilation and continue to exert antiproliferative effects. Inhibition of angiotensin II by moexipril decreases remodeling effects on the cardiovascular system. Indirectly, angiotensin II stimulates of the production of

endothelin Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute ...

1 and 3 (ET1, ET3) and the transforming growth factor beta-1 ( TGF-β1), all of which have tissue proliferative effects that are blocked by the actions of moexipril. The antiproliferative effects of moexipril have also been demonstrated by ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...

'' studies where moexipril inhibits the estrogen-stimulated growth of neonatal cardiac

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

in rats. Other ACE inhibitors have also been found to produce these actions, as well.

Pharmacology

Moexipril is available as a prodrug moexipril hydrochloride, and is metabolized in the liver to form the pharmacologically active compound moexiprilat. Formation of moexiprilat is caused by hydrolysis of an

ethyl ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides are ...

group. Moexipril is incompletely absorbed after oral administration, and its

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. ...

is low. The long pharmacokinetic

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...

and persistent ACE inhibition of moexipril allows once-daily administration. Moexipril is highly

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves li ...

, and is in the same hydrophobic range as

quinapril Quinapril, sold under the brand name Accupril among others, is a medication used to treat high blood pressure (hypertension), heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken ...

benazepril Benazepril, sold under the brand name Lotensin among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Vers ...

, and

ramipril Ramipril, sold under the brand name Altace among others, is an ACE inhibitor type medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It can also be used as a preventative medication in patients over 55 yea ...

. Lipophilic ACE inhibitors are able to penetrate membranes more readily, thus tissue ACE may be a target in addition to plasma ACE. A significant reduction in tissue ACE (lung, myocardium, aorta, and kidney) activity has been shown after moexipril use. It has additional PDE4-inhibiting effects.

Synthesis

The synthesis of the all-important dipeptide-like side chain involves alkylation of the ''tert''-butyl ester of L-alanine (2) with ethyl 2-bromo-4-phenylbutanoate (1); the presominane of the desired isomer is attributable to

asymmetric induction In stereochemistry, asymmetric induction (also enantioinduction) describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the sub ...

from the adjacent chiral center. Reaction of the product with hydrogen chloride then cleaves the ''tert''-butyl group to give the half acid (3). Coupling of that acid to the secondary amine on

tetrahydroisoquinoline Tetrahydroisoquinoline (TIQ or THIQ) is an organic compound with the chemical formula C9H11N. Classified as a secondary amine, it is derived from isoquinoline by hydrogenation. It is a colorless viscous liquid that is miscible with most organic ...

(4) gives the corresponding amine. The ''tert''-butyl ester in this product is again cleaved with

hydrogen chloride The compound hydrogen chloride has the chemical formula and as such is a hydrogen halide. At room temperature, it is a colourless gas, which forms white fumes of hydrochloric acid upon contact with atmospheric water vapor. Hydrogen chloride g ...

to afford moexipril (5).

References

{{Angiotensin receptor modulators ACE inhibitors Carboxylate esters Enantiopure drugs Ethyl esters Norsalsolinol ethers Prodrugs Methoxy compounds Carboxamides Tetrahydroisoquinolines