Moexipril

Last updated
Moexipril
Moexipril.svg
Clinical data
Trade names Univasc
AHFS/Drugs.com Monograph
MedlinePlus a695018
Routes of
administration 		Oral
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 13-22%
Protein binding 90%
Metabolism Hepatic (active metabolite, moexiprilat)
Elimination half-life 1 hour; 2-9 hours (active metabolite)
Excretion 50% (faeces), 13% (urine)
Identifiers
  • (3S)-2-[(2S)-2-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-3-carboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C27H34N2O7
Molar mass 498.576 g·mol−1
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Moexipril was an angiotensin converting enzyme inhibitor (ACE inhibitor) [1] used for the treatment of hypertension and congestive heart failure. Moexipril can be administered alone or with other antihypertensives or diuretics. [2]

Contents

It works by inhibiting the conversion of angiotensin I to angiotensin II. [3]

It was patented in 1980 and approved for medical use in 1995. [4] Moexipril is available from Schwarz Pharma under the trade name Univasc. [3] [5]

Side effects

Moexipril is generally well tolerated in elderly patients with hypertension. [6] Hypotension, dizziness, increased cough, diarrhea, flu syndrome, fatigue, and flushing have been found to affect less than 6% of patients who were prescribed moexipril. [3] [6]

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, displayed decreased infarct size. [7] The cardioprotective effects of ACE inhibitors are mediated through a combination of angiotensin II inhibition and bradykinin proliferation. [8] [9] Increased levels of bradykinin stimulate in the production of prostaglandin E2 [10] and nitric oxide, [9] which cause vasodilation and continue to exert antiproliferative effects. [8] Inhibition of angiotensin II by moexipril decreases remodeling effects on the cardiovascular system. Indirectly, angiotensin II stimulates of the production of endothelin 1 and 3 (ET1, ET3) [11] and the transforming growth factor beta-1 (TGF-β1), [12] 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 studies where moexipril inhibits the estrogen-stimulated growth of neonatal cardiac fibroblasts in rats. [9] 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 group. [13] Moexipril is incompletely absorbed after oral administration, and its bioavailability is low. [14] The long pharmacokinetic half-life and persistent ACE inhibition of moexipril allows once-daily administration. [15]

Moexipril is highly lipophilic, [2] and is in the same hydrophobic range as quinapril, benazepril, and ramipril. [15] 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. [8]

It has additional PDE4-inhibiting effects. [16]

Synthesis

Moexipril synthesis: Moexipril synthesis.svg
Moexipril 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 from the adjacent chiral center. Reaction of the product with hydrogen chloride then cleaves the tert-butyl group to give the half acid (3). [19] Coupling of that acid to the secondary amine on tetrahydroisoquinoline (4) gives the corresponding amine. The tert-butyl ester in this product is again cleaved with hydrogen chloride to afford moexipril (5).

Related Research Articles

<span class="mw-page-title-main">ACE inhibitor</span> Class of medications used primarily to treat high blood pressure

Angiotensin-converting-enzyme inhibitors are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

<span class="mw-page-title-main">Renin–angiotensin system</span> Hormone system

The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS), is a hormone system that regulates blood pressure, fluid and electrolyte balance, and systemic vascular resistance.

<span class="mw-page-title-main">Angiotensin</span> Group of peptide hormones in mammals

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 adrenal cortex to promote sodium retention by the kidneys.

<span class="mw-page-title-main">Bradykinin</span> Chemical compound

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 makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin consists of nine amino acids, and is a physiologically and pharmacologically active peptide of the kinin group of proteins.

<span class="mw-page-title-main">Captopril</span> Antihypertensive drug of the ACE inhibitor class

Captopril, sold under the brand name Capoten among others, is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inhibitor found for the treatment of hypertension. It does not cause fatigue as associated with beta-blockers. Due to the adverse drug event of causing hyperkalemia, as seen with most ACE Inhibitors, the medication is usually paired with a diuretic.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Angiotensin-converting enzyme</span> Mammalian protein found in humans

Angiotensin-converting enzyme, or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II. Therefore, ACE indirectly increases blood pressure by causing blood vessels to constrict. ACE inhibitors are widely used as pharmaceutical drugs for treatment of cardiovascular diseases.

<span class="mw-page-title-main">Fosinopril</span> Antihypertensive drug of the ACE inhibitor class

Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the only phosphonate-containing ACE inhibitor marketed, by Bristol-Myers Squibb under the trade name Monopril. Fosinopril is a cascading pro-drug. The special niche for the medication that differentiates it from the other members of the ACE Inhibitor drug class is that was specifically developed for the use for patients with renal impairment. This was through manipulation of the metabolism and excretion, and is seen that fifty percent of the drug is hepatobiliary cleared, which can compensate for diminished renal clearance. The remaining fifty percent is excreted in urine. It does not need dose adjustment.

The kinin–kallikrein system or simply kinin system is a poorly understood hormonal system with limited available research. It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types. Clinical symptoms include marked weakness, tachycardia, fever, leukocytosis and acceleration of ESR.

<span class="mw-page-title-main">Ramipril</span> ACE inhibitor

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 years old to reduce the risk of having a heart attack, stroke or cardiovascular death in patients shown to be at high risk, such as some diabetics and patients with vascular disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth.

Sérgio Henrique Ferreira was a Brazilian physician and pharmacologist noted for the discovery of the bradykinin potentiating factor, which led to new and widely used anti-hypertension drugs — the ACE inhibitors.

<span class="mw-page-title-main">Perindopril</span> High blood pressure medication

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease.

The bradykinin receptor family is a group of G-protein coupled receptors whose principal ligand is the protein bradykinin.

<span class="mw-page-title-main">Aliskiren</span> Medication

Aliskiren is the first in a class of drugs called direct renin inhibitors. It is used for essential (primary) hypertension. While used for high blood pressure, other better studied medications are typically recommended due to concerns of higher side effects and less evidence of benefit.

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<span class="mw-page-title-main">Zofenopril</span> Antihypertensive drug of the ACE inhibitor class

Zofenopril (INN) is a medication that protects the heart and helps reduce high blood pressure. It is an angiotensin-converting enzyme (ACE) inhibitor.

<span class="mw-page-title-main">Teprotide</span> Chemical compound

Teprotide is nonapeptide which has been isolated from the snake Bothrops jararaca. It is an angiotensin converting enzyme inhibitor (ACE inhibitor) which inhibits the conversion of angiotensin I to angiotensin II and may potentiate some of the pharmacological actions of bradykinin. It has a molecular formula of C53H76N14O12 and has been investigated as an antihypertension agent.

<span class="mw-page-title-main">Sacubitril/valsartan</span> Combination medication

Sacubitril/valsartan, sold under the brand name Entresto, is a fixed-dose combination medication for use in heart failure. It consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. The combination is sometimes described as an "angiotensin receptor-neprilysin inhibitor" (ARNi). In 2016, the American College of Cardiology/American Heart Association Task Force recommended it as a replacement for an ACE inhibitor or an angiotensin receptor blocker in people with heart failure with reduced ejection fraction.

<span class="mw-page-title-main">Sacubitril</span> Chemical compound

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<span class="mw-page-title-main">Furegrelate</span> Chemical compound

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References

  1. ↑ Hochadel, Maryanne, ed. (2006). The AARP Guide to Pills . Sterling Publishing Company. p.  640. ISBN   978-1-4027-1740-6 . Retrieved 2009-10-09.
  2. 1 2 Belal F, Metwaly FH, Younes KM, Amer SM (2009). "Development of Membrane Electrodes for the Specific Determination of Moexipril Hydrochloride in Dosage Forms and Biological Fluids". Portugaliae Electrochimica Acta. 27 (4): 463–475. doi:10.4152/pea.200904463.
  3. 1 2 3 Rodgers K, Vinson MC, Davis MW (1996). Breakthroughs: New drug approvals of 1995 -- part 1 (Report). Vol. 140. Advanstar Communications, Inc. p. 84.
  4. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 468. ISBN   9783527607495.
  5. ↑ Banerji S (2004). "Angiotensin-Converting Enzyme Inhibitors". In Dart RC (ed.). Medical toxicology. Lippincott Williams & Wilkins. p. 647. ISBN   978-0-7817-2845-4 . Retrieved 2009-10-09.
  6. 1 2 White WB, Stimpel M (November 1995). "Long-term safety and efficacy of moexipril alone and in combination with hydrochlorothiazide in elderly patients with hypertension". Journal of Human Hypertension. 9 (11): 879–884. PMID   8583466.
  7. ↑ Rosendorff C (October 1996). "The renin-angiotensin system and vascular hypertrophy". Journal of the American College of Cardiology. 28 (4): 803–812. doi: 10.1016/s0735-1097(96)00251-3 . PMID   8837552.
  8. 1 2 3 Chrysant SG (February 1998). "Vascular remodeling: the role of angiotensin-converting enzyme inhibitors". American Heart Journal. 135 (2 Pt 2): S21–S30. doi:10.1053/hj.1998.v135.86971. PMID   9488609.
  9. 1 2 3 Hartman JC (September 1995). "The role of bradykinin and nitric oxide in the cardioprotective action of ACE inhibitors". The Annals of Thoracic Surgery. 60 (3): 789–92. doi:10.1016/0003-4975(95)00192-N. PMID   7545893.
  10. ↑ Jaiswal N, Diz DI, Chappell MC, Khosla MC, Ferrario CM (February 1992). "Stimulation of endothelial cell prostaglandin production by angiotensin peptides. Characterization of receptors". Hypertension. 19 (2 Suppl): II49–II55. doi: 10.1161/01.hyp.19.2_suppl.ii49 . PMID   1735595.
  11. ↑ Phillips PA (July 1999). "Interaction between endothelin and angiotensin II". Clinical and Experimental Pharmacology & Physiology. 26 (7): 517–8. doi:10.1046/j.1440-1681.1999.03069.x. PMID   10405777. S2CID   27296727.
  12. ↑ Youn TJ, Kim HS, Oh BH (August 1999). "Ventricular remodeling and transforming growth factor-beta 1 mRNA expression after nontransmural myocardial infarction in rats: effects of angiotensin converting enzyme inhibition and angiotensin II type 1 receptor blockade". Basic Research in Cardiology. 94 (4): 246–253. doi:10.1007/s003950050149. PMID   10505424. S2CID   24853463.
  13. ↑ Kalász H, Petroianu G, Tekes K, Klebovich I, Ludányi K, Gulyás Z (January 2007). "Metabolism of moexipril to moexiprilat: determination of in vitro metabolism using HPLC-ES-MS". Medicinal Chemistry. 3 (1): 101–106. doi:10.2174/157340607779317490. PMID   17266629.
  14. ↑ Chrysant GS, Nguyen PK (2007). "Moexipril and left ventricular hypertrophy". Vascular Health and Risk Management. 3 (1): 23–30. PMC   1994034 . PMID   17583172.
  15. 1 2 Cawello W, Boekens H, Waitzinger J, Miller U (January 2002). "Moexipril shows a long duration of action related to an extended pharmacokinetic half-life and prolonged ACE inhibition". International Journal of Clinical Pharmacology and Therapeutics. 40 (1): 9–17. doi:10.5414/cpp40009. PMID   11837383.
  16. ↑ Cameron RT, Coleman RG, Day JP, Yalla KC, Houslay MD, Adams DR, et al. (May 2013). "Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4)". Biochemical Pharmacology. 85 (9): 1297–1305. doi:10.1016/j.bcp.2013.02.026. PMC   3625111 . PMID   23473803.
  17. ↑ EP 49605,Hoefle ML, Klutchko S,"Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids, salts thereof, pharmaceutical compositions containing the derivatives or salts, and the production of the same",published 1982-04-14, assigned to Warner Lambert Co. ; M. L. Hoefle, S. Klutchko, U.S. patent 4,344,949 (1982 to Warner-Lambert).
  18. ↑ Klutchko S, Blankley CJ, Fleming RW, Hinkley JM, Werner AE, Nordin I, et al. (October 1986). "Synthesis of novel angiotensin converting enzyme inhibitor quinapril and related compounds. A divergence of structure-activity relationships for non-sulfhydryl and sulfhydryl types". Journal of Medicinal Chemistry. 29 (10): 1953–1961. doi:10.1021/jm00160a026. PMID   3020249.
  19. ↑ Kaltenbronn JS, Dejohn D, Krolls U (2009). "Synthesis of [S-(R∗,R∗)] – Ethyl Α–[(1–Carboxyethyl) Amino]–Benezenebutanoate, an Important Intermediate in the Synthesis of Angiotensin Converting Enzyme Inhibitors". Organic Preparations and Procedures International. 15 (1–2): 35–40. doi:10.1080/00304948309355428.
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