Moexipril
{{Short description|Antihypertensive drug of the ACE inhibitor class}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 407802464
| IUPAC_name = (3S)-2-[(2S)-2-
| image = Moexipril.svg
| width = 250
| tradename = Univasc
| Drugs.com = {{drugs.com|monograph|moexipril-hydrochloride}}
| MedlinePlus = a695018
| pregnancy_AU =
| pregnancy_US = D
| pregnancy_category =
| legal_AU =
| legal_CA =
| legal_UK = POM
| legal_US = Rx-only
| legal_status = Rx-only
| routes_of_administration = Oral
| bioavailability = 13-22%
| protein_bound = 90%
| metabolism = Hepatic (active metabolite, moexiprilat)
| elimination_half-life = 1 hour; 2-9 hours (active metabolite)
| excretion = 50% (faeces), 13% (urine)
| IUPHAR_ligand = 6571
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 103775-10-6
| ATC_prefix = C09
| ATC_suffix = AA13
| ATC_supplemental =
| PubChem = 91270
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB00691
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 82418
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = WT87C52TJZ
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08225
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1165
| C=27 | H=34 | N=2 | O=7
}}
Moexipril was an angiotensin converting enzyme inhibitor (ACE inhibitor){{cite book|title=The AARP Guide to Pills|editor=Hochadel, Maryanne|publisher=Sterling Publishing Company|year=2006|page=[https://archive.org/details/aarpguidetopills00hoch/page/640 640]|isbn=978-1-4027-1740-6|url=https://archive.org/details/aarpguidetopills00hoch|url-access=registration|access-date=2009-10-09}} used for the treatment of hypertension and congestive heart failure. Moexipril can be administered alone or with other antihypertensives or diuretics.{{cite journal | vauthors = Belal F, Metwaly FH, Younes KM, Amer SM | title = Development of Membrane Electrodes for the Specific Determination of Moexipril Hydrochloride in Dosage Forms and Biological Fluids. | journal = Portugaliae Electrochimica Acta | volume = 27 | issue = 4 | date = 2009 | pages = 463–475 | doi = 10.4152/pea.200904463 }}
It works by inhibiting the conversion of angiotensin I to angiotensin II.{{cite report | vauthors = Rodgers K, Vinson MC, Davis MW | title = Breakthroughs: New drug approvals of 1995 -- part 1. | publisher = Advanstar Communications, Inc. | volume = 140 | issue = 3 | date = 1996 | page = 84 }}
It was patented in 1980 and approved for medical use in 1995.{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=468 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA468 |language=en}} Moexipril is available from Schwarz Pharma under the trade name Univasc.{{cite book| vauthors = Banerji S | chapter = Angiotensin-Converting Enzyme Inhibitors | veditors = Dart RC |title=Medical toxicology|publisher=Lippincott Williams & Wilkins|year=2004|page=647|isbn=978-0-7817-2845-4|chapter-url=https://books.google.com/books?id=BfdighlyGiwC&pg=PA647|access-date=2009-10-09}}
Side effects
Moexipril is generally well tolerated in elderly patients with hypertension.{{cite journal | vauthors = White WB, Stimpel M | title = Long-term safety and efficacy of moexipril alone and in combination with hydrochlorothiazide in elderly patients with hypertension | journal = Journal of Human Hypertension | volume = 9 | issue = 11 | pages = 879–884 | date = November 1995 | pmid = 8583466 }}
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, displayed decreased infarct size.{{cite journal | vauthors = Rosendorff C | title = The renin-angiotensin system and vascular hypertrophy | journal = Journal of the American College of Cardiology | volume = 28 | issue = 4 | pages = 803–812 | date = October 1996 | pmid = 8837552 | doi = 10.1016/s0735-1097(96)00251-3 | doi-access = free }} The cardioprotective effects of ACE inhibitors are mediated through a combination of angiotensin II inhibition and bradykinin proliferation.{{cite journal | vauthors = Hartman JC | title = The role of bradykinin and nitric oxide in the cardioprotective action of ACE inhibitors | journal = The Annals of Thoracic Surgery | volume = 60 | issue = 3 | pages = 789–92 | date = September 1995 | pmid = 7545893 | doi = 10.1016/0003-4975(95)00192-N | url = }} Increased levels of bradykinin stimulate in the production of prostaglandin E2{{cite journal | vauthors = Jaiswal N, Diz DI, Chappell MC, Khosla MC, Ferrario CM | title = Stimulation of endothelial cell prostaglandin production by angiotensin peptides. Characterization of receptors | journal = Hypertension | volume = 19 | issue = 2 Suppl | pages = II49–II55 | date = February 1992 | pmid = 1735595 | doi = 10.1161/01.hyp.19.2_suppl.ii49 | doi-access = free }} 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 1 and 3 (ET1, ET3){{cite journal | vauthors = Phillips PA | title = Interaction between endothelin and angiotensin II | journal = Clinical and Experimental Pharmacology & Physiology | volume = 26 | issue = 7 | pages = 517–8 | date = July 1999 | pmid = 10405777 | doi = 10.1046/j.1440-1681.1999.03069.x | s2cid = 27296727 }} and the transforming growth factor beta-1 (TGF-β1),{{cite journal | vauthors = Youn TJ, Kim HS, Oh BH | title = 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 | journal = Basic Research in Cardiology | volume = 94 | issue = 4 | pages = 246–253 | date = August 1999 | pmid = 10505424 | doi = 10.1007/s003950050149 | s2cid = 24853463 }} 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. 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.{{cite journal | vauthors = Kalász H, Petroianu G, Tekes K, Klebovich I, Ludányi K, Gulyás Z | title = Metabolism of moexipril to moexiprilat: determination of in vitro metabolism using HPLC-ES-MS | journal = Medicinal Chemistry | volume = 3 | issue = 1 | pages = 101–106 | date = January 2007 | pmid = 17266629 | doi = 10.2174/157340607779317490 }} Moexipril is incompletely absorbed after oral administration, and its bioavailability is low.{{cite journal | vauthors = Chrysant GS, Nguyen PK | title = Moexipril and left ventricular hypertrophy | journal = Vascular Health and Risk Management | volume = 3 | issue = 1 | pages = 23–30 | date = 2007 | pmid = 17583172 | pmc = 1994034 | doi = | url = }} The long pharmacokinetic half-life and persistent ACE inhibition of moexipril allows once-daily administration.{{cite journal | vauthors = Cawello W, Boekens H, Waitzinger J, Miller U | title = Moexipril shows a long duration of action related to an extended pharmacokinetic half-life and prolonged ACE inhibition | journal = International Journal of Clinical Pharmacology and Therapeutics | volume = 40 | issue = 1 | pages = 9–17 | date = January 2002 | pmid = 11837383 | doi = 10.5414/cpp40009 }}
Moexipril is highly lipophilic, and is in the same hydrophobic range as quinapril, benazepril, and ramipril. 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.{{cite journal | vauthors = Chrysant SG | title = Vascular remodeling: the role of angiotensin-converting enzyme inhibitors | journal = American Heart Journal | volume = 135 | issue = 2 Pt 2 | pages = S21–S30 | date = February 1998 | pmid = 9488609 | doi = 10.1053/hj.1998.v135.86971 }}
It has additional PDE4-inhibiting effects.{{cite journal | vauthors = Cameron RT, Coleman RG, Day JP, Yalla KC, Houslay MD, Adams DR, Shoichet BK, Baillie GS | display-authors = 6 | title = Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4) | journal = Biochemical Pharmacology | volume = 85 | issue = 9 | pages = 1297–1305 | date = May 2013 | pmid = 23473803 | pmc = 3625111 | doi = 10.1016/j.bcp.2013.02.026 }}
Synthesis
File:Moexipril synthesis.svg| inventor = Hoefle ML, Klutchko S }}; M. L. Hoefle, S. Klutchko, {{US patent|4344949}} (1982 to Warner-Lambert).{{cite journal | vauthors = Klutchko S, Blankley CJ, Fleming RW, Hinkley JM, Werner AE, Nordin I, Holmes A, Hoefle ML, Cohen DM, Essenburg AD | display-authors = 6 | title = Synthesis of novel angiotensin converting enzyme inhibitor quinapril and related compounds. A divergence of structure-activity relationships for non-sulfhydryl and sulfhydryl types | journal = Journal of Medicinal Chemistry | volume = 29 | issue = 10 | pages = 1953–1961 | date = October 1986 | pmid = 3020249 | doi = 10.1021/jm00160a026 }}]]
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).{{cite journal|doi=10.1080/00304948309355428|title=Synthesis of [S-(R∗,R∗)] – Ethyl Α–[(1–Carboxyethyl) Amino]–Benezenebutanoate, an Important Intermediate in the Synthesis of Angiotensin Converting Enzyme Inhibitors |journal=Organic Preparations and Procedures International|volume=15|issue=1–2|pages=35–40|year=2009| vauthors = Kaltenbronn JS, Dejohn D, Krolls U }} 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).
References
{{Reflist}}
{{ACE inhibitors}}
{{Angiotensin receptor modulators}}