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Moexipril

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Moexipril

Moexipril
CAS 103775-10-6
(3S)-2-[(2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid
Manufacturers’ Codes: RS-10085
CI-925
RS-10085-197
SPM-925
RS-10085 (free base)
Molecular Formula: C27H34N2O7
Molecular Weight: 498.57
Percent Composition: C 65.04%, H 6.87%, N 5.62%, O 22.46%
Literature References: Angiotensin converting enzyme (ACE) inhibitor; dimethoxy analog of quinapril, q.v. Prepn: M. L. Hoefle, S. Klutchko, EP 49605eidem, US 4344949 (both 1982 to Warner-Lambert); S. Klutchko et al., J. Med. Chem. 29, 1953 (1986). Pharmacology: O. Edling et al., J. Pharmacol. Exp. Ther. 275, 854 (1995). GC-MS determn in plasma: W. Hammes et al., J. Chromatogr. B 670, 81 (1995). Clinical trials in hypertension: W. B. White et al., J. Hum. Hypertens. 8, 917 (1994); M. Stimpel et al., Cardiology 87, 313 (1996).
 
Derivative Type: Hydrochloride
CAS Registry Number: 82586-52-5
Manufacturers’ Codes: CI-925; RS-10085-197; SPM-925
Trademarks: Fempress (Schwarz); Perdix (Schwarz); Univasc (Schwarz)
Molecular Formula: C27H34N2O7.HCl
Molecular Weight: 535.03
Percent Composition: C 60.61%, H 6.59%, N 5.24%, O 20.93%, Cl 6.63%
Properties: Crystals from ethanol + ethyl ether, mp 141-161°. [a]D23 +34.2° (c = 1.1 in ethanol).
Melting point: mp 141-161°
Optical Rotation: [a]D23 +34.2° (c = 1.1 in ethanol)
Derivative Type: Diacid hydrochloride
CAS Registry Number: 82586-57-0
Additional Names: Moexiprilat hydrochloride
Molecular Formula: C25H30N2O7.HCl
Molecular Weight: 506.98
Percent Composition: C 59.23%, H 6.16%, N 5.53%, O 22.09%, Cl 6.99%
Properties: Prepd as the monohydrate; crystals from THF + ethanol, mp 145-170°. [a]D23 +37.8° (c = 1.1 in methanol).
Melting point: mp 145-170°
Optical Rotation: [a]D23 +37.8° (c = 1.1 in methanol)
Therap-Cat: Antihypertensive.
Keywords: ACE-Inhibitor; Antihypertensive; N-Carboxyalkyl (peptide/lactam) Derivatives.
Moexipril hydrochloride is a potent orally active nonsulfhydryl angiotensin converting enzyme inhibitor (ACE inhibitor)[1] which is used for the treatment of hypertension and congestive heart failure. Moexipril can be administered alone or with otherantihypertensives or diuretics.[2] It works by inhibiting the conversion of angiotensin I to angiotensin II.[3] Moexipril is available from Schwarz’Pharma under the trade name Univasc.[3][4]
Originally developed at Pfizer (formerly Warner-Lambert), moexipril hydrochloride was licensed to Schwarz Pharma at the end of 1989, when it was still a phase II clinical development project. Manufacturing rights to the drug were subsequently licensed to Orgamol (acquired by BASF in 2005) in Switzerland. Bayer currently distributes the product in Italy, and Hanmi has launched it in the Republic of Korea.

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.[5] Moexipril is incompletely absorbed after oral administration, and its bioavailability is low.[6] The long pharmacokinetic half-life and persistent ACE inhibition of moexipril allows once-daily administration.[7]

Moexipril is highly lipophilic,[2] and is in the same hydrophobic range as quinapril, benazepril, and ramipril.[7] 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.[9]

Side effects

Moexipril is generally well tolerated in elderly patients with hypertension.[10] 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][10]

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.[11] The cardioprotective effects of ACE inhibitors are mediated through a combination of angiotensin II inhibition and bradykininproliferation.[8][12] Increased levels of bradykinin stimulate in the production of prostaglandin E2[13] and nitric oxide,[12] 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)[14] and the transforming growth factor beta-1 (TGF-β1),[15] 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.[12] Other ACE inhibitors have also been found to produce these actions, as well.

WO 2014202659

http://www.google.com/patents/WO2014202659A1?cl=en

US4344949

http://www.google.co.in/patents/US4344949

References

  1.  Hochadel, Maryanne, ed. (2006). The AARP Guide to Pills. Sterling Publishing Company. p. 640. ISBN 978-1-4027-1740-6. Retrieved2009-10-09.
  2.  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.
  3.  Rodgers, Katie, Michael C Vinson, and Marvin W Davis. “Breakthroughs: New drug approvals of 1995 — part 1.” Advanstar Communications, Inc. 140.3 (1996): 84.
  4.  Dart, Richard C. (2004). Medical toxicology. Lippincott Williams & Wilkins. p. 647. ISBN 978-0-7817-2845-4. Retrieved 2009-10-09.
  5.  Kalasz, H, G. Petroianu, K. Tekes, I. Klebovich, K. Ludanyi, et al. “Metabolism of moexipril to moexiprilat: determination of in vitro metabolism using HPLC-ES-MS.” Medicinal Chemistry. 3 (2007): 101-106.
  6. Jump up^ Chrysant, George S, PK Nguyen. “Moexipril and left ventricular hypertrophy.” Vascular Health Risk Management. 3.1 (2007): 23-30.
  7.  Cawello W, H. Boekens, J. Waitzinger, et al. “Moexipril shows a long duration of action related to an extended pharmacokinetic half-life and prolonged ACE-inhibition.” Int J Clin Pharmacol Ther. 40 (2002): 9-17.
  8. ^ Jump up to:a b c Chrysant, SG. “Vascular remodeling: the role of angiotensin-converting enzyme inhibitors.” American Heart Journal. 135.2 (1998): 21-30.
  9. Jump up^ Cameron, RT; Coleman, RG; Day, JP; Yalla, KC; Houslay, MD; Adams, DR; Shoichet, BK; Baillie, GS (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.
  10.  White, WB, and M Stimpel. “Long-term safety and efficacy of moexipril alone and in combination with hydrochlorothiazide in elderly patients with hypertension.” Journal of human hypertension. 9.11 (1995): 879-884.
  11. Rosendorff, C. “The Renin-Angiotensin System and Vascular Hypertrophy.” Journal of the American College of Cardiology. 28 (1996): 803-812.
  12.  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.
  13.  Jaiswal, N, DI Diz, MC Chappell, MC Khosia, CM Ferrario. “Stimulation of endothelial cell prostaglandin production by angiotensin peptides. Characterization of receptors.” Hypertension. 19.2 (1992): 49-55.
  14.  Phillips, PA. “Interaction between endothelin and angiotensin II.” Clinical and Experimental Pharmacology and Physiology. 26.7. (1999): 517-518.
  15.  Youn, TJ, HS Kim, BH Oh. “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 (1999): 246-253.

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Systematic (IUPAC) name
(3S)-2-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
Clinical data
Trade names Univasc
AHFS/Drugs.com monograph
MedlinePlus a695018
Pregnancy
category
  • US: D (Evidence of risk)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 13-22%
Protein binding 90%
Metabolism Hepatic (active metabolite, moexiprilat)
Biological half-life 1 hour; 2-9 hours (active metabolite)
Excretion 50% (faeces), 13% (urine)
Identifiers
CAS Registry Number 103775-10-6 Yes
ATC code C09AA13
PubChem CID: 91270
IUPHAR/BPS 6571
DrugBank DB00691 
ChemSpider 82418 
UNII WT87C52TJZ 
KEGG D08225 Yes
ChEMBL CHEMBL1165 
Chemical data
Formula C27H34N2O7
Molecular mass 498.568 g/mol

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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