{{Short description|Pharmaceutical drug}} {{Infobox drug | IUPAC_name = 1-Ethoxy-''N''-(3-morpholino-5-oxadiazol-3-iumyl)methanimidate | image = Molsidomine.svg | image_class = skin-invert-image | alt = | caption = <!-- Clinical data --> | pronounce = | tradename = Corvasal, Corvaton, Molsidain, Molsidolat, others | Drugs.com = {{Drugs.com|international|molsidomine}} | MedlinePlus = | pregnancy_AU = <!-- A/B1/B2/B3/C/D/X --> | pregnancy_AU_comment = | pregnancy_US = <!-- A/B/C/D/X/N --> | pregnancy_category= | routes_of_administration = By mouth (tablets), intravenous infusion | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> | legal_AU_comment = | legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F--> | legal_BR_comment = | legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_DE = <!-- Anlage I, II, III --> | legal_NZ = <!-- Class A, B, C --> | legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --> | legal_US = <!-- OTC/Rx-only/Schedule I, II, III, IV, V --> | legal_UN = <!-- N I, II, III, IV / P I, II, III, IV--> | legal_status = Rx-only <!-- Pharmacokinetic data --> | bioavailability = 44–59% | protein_bound = 3–11% | metabolism = Hydrolysis | metabolites = Linsidomine | onset = | elimination_half-life = 1–2 hrs (linsidomine) | duration_of_action = | excretion = >90% renal <!-- Identifiers --> | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 25717-80-0 | class = | ATCvet = | ATC_prefix = C01 | ATC_suffix = DX12 | PubChem = 5353788 | DrugBank = DB09282 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 4090 | ChEBI = 31861 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 1256353 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D01320 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = D46583G77X <!-- Chemical and physical data --> | chemical_formula = | C=9 | H=14 | N=4 | O=4 | SMILES = [O-]C(OCC)=Nc2on[n+](N1CCOCC1)c2 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C9H14N4O4/c1-2-16-9(14)10-8-7-13(11-17-8)12-3-5-15-6-4-12/h7H,2-6H2,1H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = XLFWDASMENKTKL-UHFFFAOYSA-N | melting_point = 140 | melting_high = 141 }}
'''Molsidomine''' (trade names '''Corvasal''', '''Corvaton''' and many others) is an orally active, short acting vasodilating drug used to treat angina pectoris. Molsidomine is metabolized in the liver to the active metabolite linsidomine. Linsidomine is an unstable compound that releases nitric oxide (NO) upon decay as the actual vasodilating compound.<ref>{{cite journal | vauthors = Rosenkranz B, Winkelmann BR, Parnham MJ | title = Clinical pharmacokinetics of molsidomine | journal = Clinical Pharmacokinetics | volume = 30 | issue = 5 | pages = 372–84 | date = May 1996 | pmid = 8743336 | doi = 10.2165/00003088-199630050-00004 }}</ref>
==Medical uses== Molsidomine is used for the prevention and long-term treatment of stable and unstable angina pectoris, with or without left heart failure. It is also used to treat angina in the context of an acute myocardial infarction.<ref name="AustriaCodex" /><ref name="Dinnendahl">{{cite book|title=Arzneistoff-Profile| veditors = Dinnendahl V, Fricke U |publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|date=2010|edition=24|volume=7|at=Molsidomin|isbn=978-3-7741-9846-3|language=German}}</ref>
==Contraindications== The drug must not be used in patients with acute cardiac arrest or severe hypotension (low blood pressure), during lactation, and in combination with PDE5 inhibitors such as sildenafil.<ref name="AustriaCodex" /><ref name="Dinnendahl" />
==Side effects== The most common adverse effects are headache, which occurs in 10–25% of patients, and low blood pressure. Side effects occurring in fewer than 1% of patients include dizziness, nausea, reflex tachycardia (fast heartbeat), hypersensitivity reactions, as well as thrombocytopenia (low blood platelet count) in rare cases.<ref name="AustriaCodex" /><ref name="Dinnendahl" />
== Interactions ==
The blood pressure lowering effect of molsidomine can be amplified significantly by PDE5 inhibitors, potentially leading to fainting or myocardial infarction, and to a lesser extent by other antihypertensive drugs such as beta blockers, calcium channel blockers, or other nitrovasodilators. Ergolines can antagonise the effects of molsidomine.<ref name="AustriaCodex" /><ref name="Dinnendahl" />
==Pharmacology== ===Mechanism of action=== {{See|Biological functions of nitric oxide}} Molsidomine belongs to the drug class of nitrovasodilators. It releases NO, which acts as a gaseous signaling molecule, relaxing the smooth muscles of blood vessels.<ref name="Mutschler">{{Cite book| vauthors = Mutschler E, Schäfer-Korting M |title=Arzneimittelwirkungen |language=German |location=Stuttgart |publisher=Wissenschaftliche Verlagsgesellschaft |year=2001|edition=8|page=558|isbn=978-3-8047-1763-3}}</ref><ref name="stryer">{{cite book| vauthors = Stryer L | title = Biochemistry | edition = 4th | publisher = W.H. Freeman and Company|year = 1995| page = 732| isbn = 978-0-7167-2009-6}}</ref>
===Pharmacokinetics=== The substance is quickly and almost completely (>90%) absorbed from the gut. Molsidomine is a prodrug that is hydrolysed to linsidomine (SIN-1) in the liver via first-pass effect, which subsequently releases NO. 44–59% of molsidomine reach the bloodstream in unchanged form, 3–11% of which are bound to plasma proteins. Both molsidomine and linsidomine reach their highest concentrations in the blood plasma after one to two hours. Linsidomine has a biological half-life of one to two hours. More than 90% are excreted via the kidney.<ref name="AustriaCodex">{{cite book|title=Austria-Codex|at=Molsidolat 4 mg-Tabletten|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2018|isbn=978-3-85200-196-8|language=German}}</ref><ref name="Mutschler" /> thumb|center|700px|NO release from molsidomine<ref name="Mutschler" />
==Chemistry== [[File:Molsidomine.png|thumb|The mesoionic structure of molsidomine]] Molsidomine and linsidomine are sydnone imines, a class of mesoionic heterocyclic aromatic chemical compounds. Molsidomine melts at {{convert|140|–|141|°C|°F}}, is freely soluble in chloroform, soluble in aqueous hydrochloric acid, ethanol, ethyl acetate and methanol, sparingly soluble in water and acetone, and very slightly soluble in diethyl ether and petroleum ether. It is stable in aqueous solutions at pH 5–7, but not in alkaline solutions. Its absorption maximum is in the near ultraviolet, at 326 nm, in chloroform. The substance is sensitive to ultraviolet light at wavelengths shorter than 320 nm.<ref name="Dinnendahl" />
===Synthesis=== [[File:Molsidomine synthesis.svg|thumb|center|700px|[https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-13-0172 Thieme] Synthesis:<ref>[http://ci.nii.ac.jp/els/110003632546.pdf?id=ART0004139913&type=pdf&lang=en&host=cinii&order_no=&ppv_type=0&lang_sw=&no=1438091494&cp= Chemical and Pharmaceutical Bulletin 19(1), 72-79, 1971-01-25.]</ref> Patents:<ref>DE1695897 idem K Masuda & Y Imashiro, {{US patent|3769283}} & US3812128 (1973 & 1974 to Takeda Pharmaceutical Co Ltd).</ref>]] Its synthesis starts by reacting 1-aminomorpholine with formaldehyde and hydrogen cyanide to give '''2'''. Nitrosation gives the N-nitroso analog ('''3''') which cyclizes to the Linsidomine ('''4''') on treatment with anhydrous acid. Formation of the ethyl urethane is then made possible by reacting linsidomine with ethyl chloroformate.
Also see a related structure called Ciclosidomine.
==History== The substance was first synthesised at Takeda in 1970. Its antihypertensive and vasodilating properties were discovered the same year.<ref>{{cite book| vauthors = Müller-Jahncke WB, Friedrich C, Meyer U |title=Arzneimittelgeschichte|edition=2nd|publisher=Wiss. Verl.-Ges|location=Stuttgart|date=2005-01-01|page=163|isbn=9783804721135}}</ref>
== References == {{Reflist}}
{{Vasodilators used in cardiac diseases}} {{Nitric oxide signaling}}
Category:Vasodilators Category:4-Morpholinyl compounds Category:Carbamates Category:Oxadiazoles Category:Ethyl esters