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{{Short description|Chemical compound}} |
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{{Drugbox |
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{{Drugbox |
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| IUPAC_name = Ethyl ''N''-vinyl]-3-methyl-1-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-3''H''-benzoisobenzofuran-7-yl]carbamate |
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| Watchedfields = changed |
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| synonyms = SCH-530348 |
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| verifiedrevid = 407843385 |
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| image = SCH-530348.png |
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| IUPAC_name = Ethyl ''N''-vinyl]-3-methyl-1-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-3''H''-benzoisobenzofuran-7-yl]carbamate |
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| CAS_number = 618385-01-6 |
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| image = Vorapaxar structure.svg |
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| ATC_prefix = |
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| width = 230 |
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| ATC_suffix = |
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| alt = |
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| PubChem = 10077130 |
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| image2 = Vorapaxar ball-and-stick model.png |
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| DrugBank = |
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| width2 = 250 |
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| C=29|H=33|F=1|N=2|O=4 |
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| alt2 = |
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| molecular_weight = 492.58 g/mol |
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| bioavailability = |
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<!--Clinical data--> |
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| protein_bound = |
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| tradename = Zontivity |
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| metabolism = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| elimination_half-life = |
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| pregnancy_category = |
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| excretion = |
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| routes_of_administration = ] |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| ATC_prefix = B01 |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| ATC_suffix = AC26 |
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| pregnancy_category= |
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
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| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
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| legal_CA = Rx-only |
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
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| legal_CA_comment = <ref>{{cite web | title=Health Canada New Drug Authorizations: 2016 Highlights | website=] | date=14 March 2017 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-canada-new-drug-authorizations-2016-highlights.html | access-date=7 April 2024}}</ref> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
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| legal_status = |
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| legal_US = Rx-only |
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| routes_of_administration = |
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| legal_status = |
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<!--Pharmacokinetic data--> |
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| bioavailability = ~100%<ref name="zontivity">{{cite web|title=ZONTIVITY™ (vorapaxar) Tablets 2.08 mg, for oral use. Full Prescribing Information|url=http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_pi.pdf|publisher=Merck & Co., Inc. Initial U.S. Approval: 05/2014.|access-date=17 June 2014}}</ref> |
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| protein_bound = ≥99% |
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| metabolism = hepatic (] and ]) |
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| elimination_half-life = 5–13 days |
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| excretion = feces (58%), urine (25%) |
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<!--Identifiers--> |
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| IUPHAR_ligand = 4047 |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 618385-01-6 |
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| melting_point = 278 |
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| PubChem = 10077130 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII = ZCE93644N2 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI = 82702 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 493982 |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| ChemSpiderID = 8252668 |
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| synonyms = SCH-530348 |
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<!--Chemical data--> |
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| C=29 | H=33 | F=1 | N=2 | O=4 |
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| smiles = Fc1cccc(c1)c2ccc(nc2)\C=C\43(C(NC(=O)OCC)CC3)C5C(=O)O(45)C |
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| StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChI = 1S/C29H33FN2O4/c1-3-35-29(34)32-23-10-11-24-20(14-23)15-26-27(17(2)36-28(26)33)25(24)12-9-22-8-7-19(16-31-22)18-5-4-6-21(30)13-18/h4-9,12-13,16-17,20,23-27H,3,10-11,14-15H2,1-2H3,(H,32,34)/b12-9+/t17-,20+,23-,24-,25+,26-,27+/m1/s1 |
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChIKey = ZBGXUVOIWDMMJE-QHNZEKIYSA-N |
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}} |
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}} |
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'''Vorapaxar''' (formerly SCH-530,348) is a ] receptor (]) antagonist based on the natural product ]. Discovered by ] and currently being developed by ], it is a experimental pharmaceutical treatment for acute coronary syndrome chest pain caused by coronary artery disease.<ref name=chack>{{cite journal|author= Samuel Chackalamannil|title=Discovery of a Novel, Orally Active Himbacine-Based Thrombin Receptor Antagonist (SCH 530348) with Potent Antiplatelet Activity|journal=]|year=2008|doi =10.1021/jm800180e|volume= 51|pages= 3061}}</ref> |
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'''Vorapaxar''' (brand name '''Zontivity''', formerly known as '''SCH 530348''') is a ] receptor (], PAR-1) ] based on the natural product ], discovered by ] and developed by ]<ref name="pmid18447380">{{cite journal | vauthors = Chackalamannil S, Wang Y, Greenlee WJ, Hu Z, Xia Y, Ahn HS, Boykow G, Hsieh Y, Palamanda J, Agans-Fantuzzi J, Kurowski S, Graziano M, Chintala M | display-authors = 6 | title = Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 11 | pages = 3061–3064 | date = June 2008 | pmid = 18447380 | doi = 10.1021/jm800180e }}</ref> |
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==Medical uses== |
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In January 2011, clinical trials being conducted by Merck were halted for patients with stroke and mild heart conditions.<ref>, '']'', January 13, 2011</ref> Merck is uncertain whether further development of vorapaxar will continue. |
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Vorapaxar is used for persons with a history of ] (heart attack) or persons with ]. Studies have shown that this medication can reduce the rate of combined endpoint cardiovascular death, MI, stroke, and urgent coronary revascularization.<ref name="zontivity"/> |
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==Contraindications== |
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==References== |
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Vorapaxar is contraindicated for people with a history of ], ], or ].<ref name="zontivity"/> |
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{{reflist}} |
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In studies of vorapaxar on persons with prior ], there was an increased risk of intracranial hemorrhage without an improvement in major vascular events. Vorapaxar possesses a long half-life, which is problematic because there is currently no treatment to reverse the antiplatelet effects of vorapaxar.<ref name="zontivity"/> This family of medication, PAR-1 antagonists in general, has been associated with an increased risk of intracranial bleeding, as demonstrated by a ] of data that studied 42,000 patients with history of ] ] or ] comparing the medication and a placebo.<ref name="pmid23396280">{{cite journal | vauthors = Morrow DA, Alberts MJ, Mohr JP, Ameriso SF, Bonaca MP, Goto S, Hankey GJ, Murphy SA, Scirica BM, Braunwald E | display-authors = 6 | title = Efficacy and safety of vorapaxar in patients with prior ischemic stroke | journal = Stroke | volume = 44 | issue = 3 | pages = 691–698 | date = March 2013 | pmid = 23396280 | doi = 10.1161/STROKEAHA.111.000433 | s2cid = 25848104 | collaboration = Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–TIMI 50 Steering Committee and Investigators | doi-access = free }}</ref> |
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==Drug interactions== |
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==External links== |
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Vorapaxar is eliminated primarily via metabolism by the ] enzymes. It is best to avoid strong CYP3A4 inhibitors, such as ], ], ], ], ], ], ], ], ], ], ], ], and ]. ] inducers, such as ], ], ], and ], should also be avoided.<ref name="zontivity"/> |
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==Dose adjustment== |
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No dose adjustment is required in persons with ].<ref name="zontivity"/> |
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No dose adjustment is required in persons with mild and moderate ]. If the person has severe hepatic impairment, vorapaxar is not recommended due to the risk of bleeding.<ref name="zontivity"/> |
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==Mechanism of action== |
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Vorapaxar is an antiplatelet drug of the PAR-1 antagonist family. It functions by inhibiting ]-related ]. This mechanism works by a different pathway from other antiplatelet medications, such as aspirin and ]. Vorapaxar does not affect ADP-mediated platelet aggregation, coagulation parameters, or ].<ref>{{cite journal | vauthors = Baker NC, Lipinski MJ, Lhermusier T, Waksman R | title = Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting about vorapaxar | journal = Circulation | volume = 130 | issue = 15 | pages = 1287–1294 | date = October 2014 | pmid = 25287768 | doi = 10.1161/circulationaha.114.011471 | s2cid = 26737510 | doi-access = }}</ref> |
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==Storage== |
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Vorapaxar can be stored at {{convert|20–25|C|F}}. It is best to store vorapaxar in original packaging with the bottle tightly closed and to avoid moisture.<ref name="zontivity"/> |
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==History== |
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In January 2011, clinical trials being conducted by Merck were halted for patients with stroke and mild heart conditions due to an increase in brain bleeding.<ref>{{cite web | vauthors = Cortez MF, Randall T | url = https://www.bloomberg.com/news/2011-01-13/merck-blood-thinner-study-ends-in-stroke-patients-limiting-possible-sales.html | title = Merck Blood Thinner Studies Halted in Select Patients | work = ] | date = 13 January 2011 }}</ref> In a ] ] comparing vorapaxar with placebo in addition to standard therapy in patients who had acute coronary syndromes, there was no significant reduction in a composite end point of death from cardiovascular causes, ], stroke, recurrent ] with rehospitalization, or urgent ] ]. However, there was increased risk of major bleeding.<ref name=Tricoci>{{cite journal | vauthors = Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F, White HD, Aylward PE, Wallentin L, Chen E, Lokhnygina Y, Pei J, Leonardi S, Rorick TL, Kilian AM, Jennings LH, Ambrosio G, Bode C, Cequier A, Cornel JH, Diaz R, Erkan A, Huber K, Hudson MP, Jiang L, Jukema JW, Lewis BS, Lincoff AM, Montalescot G, Nicolau JC, Ogawa H, Pfisterer M, Prieto JC, Ruzyllo W, Sinnaeve PR, Storey RF, Valgimigli M, Whellan DJ, Widimsky P, Strony J, Harrington RA, Mahaffey KW | display-authors = 6 | title = Thrombin-receptor antagonist vorapaxar in acute coronary syndromes | journal = The New England Journal of Medicine | volume = 366 | issue = 1 | pages = 20–33 | date = January 2012 | pmid = 22077816 | doi = 10.1056/NEJMoa1109719 | hdl-access = free | hdl = 2445/49763 }}</ref> A trial published in February 2012 found no change in ] while decreasing the risk of cardiac death and increasing the risk of major bleeding, including intracranial hemorrhages. After two years, the data and safety monitoring board recommended discontinuation of the study treatment in people with a history of stroke owing to the risk of intracranial hemorrhage. |
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The TRA 2°P–TIMI 50 study of vorapaxar was carried out in patients who had previously experienced a heart attack, stroke, or who had ] (PAD). In this three-year study, the addition of vorapaxar to ] (aspirin and/or an ADP antagonist such as clopidogrel) significantly reduced the risk of the primary composite endpoint of cardiovascular death, heart attack, stroke, or urgent coronary revascularization by 12 percent compared to placebo plus standard of care. Vorapaxar showed the most promising results among patients with a history of heart attack. Among these patients, the drug reduced the relative risk of cardiovascular death, heart attack, or stroke by 20 percent. There was an increase in moderate or severe bleeding, but no statistically significant increase in fatal bleeding.<ref>{{cite journal | vauthors = Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP, Fox KA, Lipka LJ, Liu X, Nicolau JC, Ophuis AJ, Paolasso E, Scirica BM, Spinar J, Theroux P, Wiviott SD, Strony J, Murphy SA | display-authors = 6 | title = Vorapaxar in the secondary prevention of atherothrombotic events | journal = The New England Journal of Medicine | volume = 366 | issue = 15 | pages = 1404–1413 | date = April 2012 | pmid = 22443427 | doi = 10.1056/NEJMoa1200933 | hdl-access = free | s2cid = 205094316 | hdl = 10447/94482 }}</ref> |
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Vorapaxar was recommended for ] on January 15, 2014,<ref name=Merck>{{cite web|title=Merck Statement on FDA Advisory Committee for Vorapaxar, Merck's Investigational Antiplatelet Medicine |date = 15 January 2014 |url=http://www.mercknewsroom.com/news-release/research-and-development-news/merck-statement-fda-advisory-committee-vorapaxar-mercks-i | archive-url = https://web.archive.org/web/20140120162709/http://www.mercknewsroom.com/news-release/research-and-development-news/merck-statement-fda-advisory-committee-vorapaxar-mercks-i | archive-date = 20 January 2014 |publisher=Merck|access-date=16 January 2014}}</ref> and obtained it on May 5, 2014. |
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== References == |
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{{reflist}} |
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== Further reading == |
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{{refbegin}} |
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* {{cite journal| vauthors = Borman S | title = Hopes Ride on Drug Candidates: Researchers reveal potential new medicines for thrombosis, anxiety, diabetes, and cancer |url = http://pubs.acs.org/email/cen/html/021806150931.html |journal = ] | year = 2005 | volume = 83 |issue = 16 |pages = 40–44| doi = 10.1021/cen-v083n016.p040 }} |
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{{refend}} |
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{{Antithrombotics}} |
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{{Antithrombotics}} |
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