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]
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 ofmyocardial infarction, displayed decreased infarct size.[7] The cardioprotective effects of ACE inhibitors are mediated through a combination of angiotensin II inhibition andbradykinin proliferation.[8][9] Increased levels of bradykinin stimulate in the production ofprostaglandin 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 ofendothelin 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 byin vitro studies where moexipril inhibits the estrogen-stimulated growth of neonatal cardiacfibroblasts in rats.[9] Other ACE inhibitors have also been found to produce these actions, as well.
Moexipril is available as aprodrug moexipril hydrochloride, and is metabolized in the liver to form the pharmacologically active compound moexiprilat. Formation of moexiprilat is caused by hydrolysis of anethyl ester group.[13] Moexipril is incompletely absorbed after oral administration, and itsbioavailability is low.[14] The long pharmacokinetichalf-life and persistent ACE inhibition of moexipril allows once-daily administration.[15]
Moexipril is highlylipophilic,[2] and is in the same hydrophobic range asquinapril,benazepril, andramipril.[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]
The synthesis of the all-important dipeptide-like side chain involves alkylation of thetert-butyl ester ofL-alanine (2) with ethyl 2-bromo-4-phenylbutanoate (1); the presominane of the desired isomer is attributable toasymmetric induction from the adjacent chiral center. Reaction of the product with hydrogen chloride then cleaves thetert-butyl group to give the half acid (3).[19] Coupling of that acid to the secondary amine ontetrahydroisoquinoline (4) gives the corresponding amine. Thetert-butyl ester in this product is again cleaved withhydrogen chloride to afford moexipril (5).
^abBelal 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.
^abcRodgers K, Vinson MC, Davis MW (1996). Breakthroughs: New drug approvals of 1995 -- part 1 (Report). Vol. 140. Advanstar Communications, Inc. p. 84.
^abWhite 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.PMID8583466.
^abcChrysant 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.PMID9488609.
^abcHartman 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.PMID7545893.
^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.PMID10505424.S2CID24853463.
^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.PMID17266629.
^abCawello 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.PMID11837383.
^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 toWarner Lambert Co.; M. L. Hoefle, S. Klutchko,U.S. patent 4,344,949 (1982 toWarner-Lambert).
^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.PMID3020249.
^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.
N
Y (what is this?) (verify)
