| Revision as of 05:28, 12 August 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{chembox}} (no changed fields - added verified revid - updated 'DrugBank_Ref', 'ChEMBL_Ref', 'ChEBI_Ref', 'ChEBI_Ref') per Chem/Drugbox validation (report [[Wikipedia_talk:WikiProject_C |
Latest revision as of 07:36, 24 November 2024 edit Boghog (talk | contribs)Autopatrolled, Extended confirmed users, IP block exemptions, New page reviewers, Pending changes reviewers, Rollbackers, Template editors137,536 edits →External links: + cat |
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{{Short description|Chemical compound}} |
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{{chembox |
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{{Use American English|date=August 2023}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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{{Use dmy dates|date=August 2023}} |
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| UNII = P7T269PR6S |
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{{cs1 config |name-list-style=vanc |display-authors=6}} |
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| verifiedrevid = 437192911 |
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{{Infobox drug |
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| ImageFile = Anacetrapib.svg |
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| Verifiedfields = changed |
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| ImageSize = |
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| verifiedrevid = 444391072 |
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| IUPACName = (4''S'',5''R'')-5--3-({2--5-(trifluoromethyl)phenyl}methyl)-4-methyl-1,3-oxazolidin-2-one |
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| image = Selexipag.svg |
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| OtherNames = |
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| width = |
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| Section1 = {{Chembox Identifiers |
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| alt = |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| caption = |
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| ChemSpiderID = 9731205 |
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| InChI = 1/C30H25F10NO3/c1-14(2)22-11-23(25(43-4)12-24(22)31)21-6-5-18(28(32,33)34)9-17(21)13-41-15(3)26(44-27(41)42)16-7-19(29(35,36)37)10-20(8-16)30(38,39)40/h5-12,14-15,26H,13H2,1-4H3/t15-,26-/m0/s1 |
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<!-- Clinical data --> |
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| InChIKey = MZZLGJHLQGUVPN-HAWMADMCBN |
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| pronounce = |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| tradename = Uptravi |
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| StdInChI = 1S/C30H25F10NO3/c1-14(2)22-11-23(25(43-4)12-24(22)31)21-6-5-18(28(32,33)34)9-17(21)13-41-15(3)26(44-27(41)42)16-7-19(29(35,36)37)10-20(8-16)30(38,39)40/h5-12,14-15,26H,13H2,1-4H3/t15-,26-/m0/s1 |
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| Drugs.com = |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| MedlinePlus = |
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| StdInChIKey = MZZLGJHLQGUVPN-HAWMADMCSA-N |
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| DailyMedID = Selexipag |
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| CASNo = 875446-37-0 |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| PubChem = 11556427 |
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| pregnancy_AU_comment = |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| pregnancy_category= |
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| KEGG = D08855 |
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| routes_of_administration = ], ] |
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| SMILES = O=C2O(c1cc(cc(c1)C(F)(F)F)C(F)(F)F)(N2Cc4c(c3cc(c(F)cc3OC)C(C)C)ccc(c4)C(F)(F)F)C |
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| class = ] agonist |
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| ATC_prefix = B01 |
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| ATC_suffix = AC27 |
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| ATC_supplemental = |
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<!-- Legal status --> |
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| legal_AU = S4 |
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| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2016 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2016 | access-date=10 April 2023 | archive-date=10 April 2023 | archive-url=https://web.archive.org/web/20230410065503/https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2016 | url-status=live }}</ref> |
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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
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| legal_BR_comment = |
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| legal_CA = Rx-only |
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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_DE = <!-- Anlage I, II, III or Unscheduled --> |
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| legal_DE_comment = |
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| legal_NZ = <!-- Class A, B, C --> |
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| legal_NZ_comment = |
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| 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 --> |
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| legal_UK_comment = |
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| legal_US = Rx-only |
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| legal_US_comment = <ref name="Uptravi FDA label">{{cite web | title=Uptravi- selexipag tablet, coated Uptravi Titration Pack- selexipag kit | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a7a23b87-f892-4e2c-8e2e-ebf841220f90 | access-date=30 July 2021 | archive-date=30 July 2021 | archive-url=https://web.archive.org/web/20210730203137/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a7a23b87-f892-4e2c-8e2e-ebf841220f90 | url-status=live }}</ref> |
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| legal_EU = Rx-only |
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| legal_EU_comment = <ref name="Uptravi EPAR">{{cite web | title=Uptravi EPAR | website=European Medicines Agency | date=1 July 2022 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/uptravi | access-date=27 August 2023 | archive-date=12 May 2021 | archive-url=https://web.archive.org/web/20210512214620/https://www.ema.europa.eu/en/medicines/human/EPAR/uptravi | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> |
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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
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| legal_UN_comment = |
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| legal_status = <!-- For countries not listed above --> |
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<!-- Pharmacokinetic data --> |
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| bioavailability = 49% |
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| protein_bound = 99% |
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| metabolism = Activation by ]s, inactivation by ] and others |
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| metabolites = ACT-333679, the free acid (]) |
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| onset = |
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| elimination_half-life = 0.8–2.5 h (selexipag) and 6.2–13.5 h (ACT-333679) |
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| duration_of_action = |
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| excretion = 93% faeces |
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<!-- Identifiers --> |
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| CAS_number_Ref = |
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| CAS_number = 475086-01-2 |
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| CAS_supplemental = |
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| PubChem = 9913767 |
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| IUPHAR_ligand = 7552 |
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| DrugBank_Ref = |
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| DrugBank = DB11362 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 8089417 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 5EXC0E384L |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D09994 |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 90844 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 238804 |
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| NIAID_ChemDB = |
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| PDB_ligand = |
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| synonyms = ACT-293987, NS-304 |
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<!-- Chemical and physical data --> |
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| IUPAC_name = 2-{4-butoxy}-''N''-(methanesulfonyl)acetamide |
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| chemical_formula_ref = |
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| C=26 | H=32 | N=4 | O=4 | S=1 |
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| SMILES = CC(C)N(CCCCOCC(=O)NS(=O)(=O)C)C1=CN=C(C(=N1)C2=CC=CC=C2)C3=CC=CC=C3 |
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| StdInChI = 1S/C26H32N4O4S/c1-20(2)30(16-10-11-17-34-19-24(31)29-35(3,32)33)23-18-27-25(21-12-6-4-7-13-21)26(28-23)22-14-8-5-9-15-22/h4-9,12-15,18,20H,10-11,16-17,19H2,1-3H3,(H,29,31) |
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| StdInChI_comment = {{chemspidercite|correct|chemspider}} |
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| StdInChIKey = QXWZQTURMXZVHJ-UHFFFAOYSA-N |
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| density = |
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}} |
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| Section2 = {{Chembox Properties |
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| Formula = C<sub>30</sub>H<sub>25</sub>F<sub>10</sub>NO<sub>3</sub> |
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| MolarMass = 637.51 g·mol<sup>−1</sup> |
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| Appearance = |
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}} |
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| Section3 = {{Chembox Hazards |
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| MainHazards = |
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}} |
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}} |
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'''Anacetrapib''' (],<ref name=USAN>{{cite web |
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| url = http://www.ama-assn.org/ama1/pub/upload/mm/365/anacetrapib.pdf | title = Statement on a nonproprietary name adopted by the USAN Council: Anacetrapib | year = 2007 | accessdate = 2008-01-19 | publisher = ]}}</ref> ]; codenamed '''MK-0859''', ]) is a ] being developed to treat ] (elevated cholesterol levels) and prevent ]. |
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'''Selexipag''', sold under the brand name '''Uptravi''', is a medication developed by ] for the treatment of ] (PAH).<ref name="Uptravi FDA label" /><ref name="Uptravi EPAR" /> Selexipag and its ], ] (or MRE-269, the free ]), are ]s of the ], which leads to ] in the pulmonary circulation.<ref>{{cite journal | vauthors = Sitbon O, Morrell N | title = Pathways in pulmonary arterial hypertension: the future is here | journal = European Respiratory Review | volume = 21 | issue = 126 | pages = 321–327 | date = December 2012 | pmid = 23204120 | pmc = 9487224 | doi = 10.1183/09059180.00004812 | doi-access = free }}</ref> It is taken ] or administered intravenously.<ref name="Uptravi FDA label" /><ref>{{cite press release | title=Uptravi (selexipag) Receives FDA Approval for Intravenous Use in Adult Patients with Pulmonary Arterial Hypertension (PAH) | website=Janssen Pharmaceutical Companies | date=30 July 2021 | url=https://www.jnj.com/uptravi-selexipag-receives-fda-approval-for-intravenous-use-in-adult-patients-with-pulmonary-arterial-hypertension-pah | access-date=30 July 2021}}</ref> |
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==Clinical trials== |
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At the 16th International Symposium on Drugs Affecting Lipid Metabolism (New York, Oct 4-7, 2007), Merck reported on a Phase IIb study. The eight week study reported dosage correlated reduction in LDL-C and increases in HDL-C levels with no corresponding increases in blood pressure in any cohort. The increase in HDL was particularly significant, averaging 44 percent, 86 percent, 139 percent and 133 percent at doses of 10 mg, 40 mg, 150 mg and 300 mg. |
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The most common side effects include headache, diarrhea, nausea and vomiting, jaw pain, myalgia (muscle pain), pain in the limbs, arthralgia (joint pain) and flushing.<ref name="Uptravi EPAR" /> |
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It is available as a ].<ref>{{cite web | title=Competitive Generic Therapy Approvals | website=U.S. ] (FDA) | date=29 June 2023 | url=https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | access-date=29 June 2023 | archive-date=29 June 2023 | archive-url=https://web.archive.org/web/20230629233651/https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | url-status=live }}</ref> |
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== Medical uses == |
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Selexipag is ] for the treatment of pulmonary arterial hypertension.<ref name="Uptravi FDA label" /><ref name="Uptravi EPAR" /> |
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==Contraindications== |
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In the European Union, use of selexipag together with strong inhibitors of the liver enzyme ], such as ], is contraindicated because it increases concentrations of selexipag twofold, and its active metabolite 11-fold, potentially leading to more adverse effects.<ref name="Uptravi EPAR" /><ref>{{citation|title=Information des Bundesamtes für Sicherheit im Gesundheitswesen zu Uptravi|publisher=Österreichisches Bundesamt für Sicherheit im Gesundheitswesen|language=de|date=2017-06-07}}</ref> |
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==Adverse effects== |
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The adverse effects of selexipag are similar to those of intravenous ]s used for pulmonary arterial hypertension. Common side effects include headache and jaw pain. An increased risk for ] has also been noted in people taking selexipag.<ref name="EMA" /> |
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==Pharmacology== |
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===Mechanism of action=== |
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]]] |
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Selexipag and its ] ACT-333679 act on the prostacyclin receptor of lung tissue, with the latter being 37-fold more potent. They are selective for the prostacyclin receptor. Binding to this receptor leads to three major effects: increased ] of the arteries, decreased ] and inhibition of ] aggregation,<ref name="EMA" /> all beneficial in the treatment of pulmonary arterial hypertension. |
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{{clear left}} |
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===Pharmacokinetics=== |
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Selexipag is quickly absorbed from the gut and ] in the intestines and the liver to ACT-333679 by ]s. Absolute ] is about 49%, most likely because of a high ]. Highest concentrations in the ] are reached after one to three hours for selexipag and after three to four hours for the active metabolite. When in the circulation, about 99% of both substances are bound to ], namely to ] and ] to equal amounts.<ref name="EMA" /> |
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The liver enzymes ] and, to a lesser extent, ], ] and ] the active substance, thereby inactivating it. Besides, ACT-333679 is ] by the enzymes ] and ]. The ] of selexipag is 0.8 to 2.5 hours, that of the active metabolite is 6.2 to 13.5 hours.<ref name="EMA" /> |
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Merck performed a of anacetrapib, with the results presented in 2009<ref>{{cite journal |
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|author=Bloomfield D, Carlson GL, Sapre A ''et al.'' |
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|title=Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and co-administered with atorvastatin in dyslipidemic patients |
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|journal=Am. Heart J. |
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|volume=157 |pages=352–360 |
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|year=2009 |month=October |
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|pmid=19185645 |doi=10.1016/j.ahj.2008.09.022 |
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|url=http://www.ahjonline.com/article/PIIS0002870308008284/fulltext |
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}}</ref> |
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== Chemistry == |
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===Phase III trial (DEFINE)=== |
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Merck started a Phase III trial to assess the drug's effects on LDL, HDL, clinically measurable cardiovascular events, and safety;<ref>{{cite web |
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| title = Phase III Study to Assess the Tolerability and Efficacy of Anacetrapib in Patients With Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease (DEFINE) |
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| url = http://clinicaltrials.gov/ct2/show/NCT00685776 |
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| work = ClinicalTrials.gov |
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| publisher = U.S. NIH |
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}}</ref> It was code-named DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib), and was described as a medium sized safety and efficacy trial.<ref>{{cite journal |
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|author=Cannon CP, Dansky HM, Davidson M, ''et al.'' |
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|title=Design of the DEFINE trial: determining the Efficacy and tolerability of CETP Inhibition with AnacEtrapib |
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|journal=Am. Heart J. |
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|volume=158 |issue=4 |pages=513–519.e3 |
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|year=2009 |month=October |
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|pmid=19781408 |doi=10.1016/j.ahj.2009.07.028 |
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|url=http://www.ncbi.nlm.nih.gov/pubmed/19781408 |
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}}</ref> |
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=== Synthesis === |
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Early results from the DEFINE trial were presented on November 17 at AHA2010, a meeting of the ]. At 100 mg dosage, LDL decreased by 36% while HDL increased by 138%. Systolic blood pressure showed no increase, and there was no association with increased CVD death or events. |
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] |
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<ref> |
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The synthesis of celexipag begins from two inexpensive compounds, ] and ], condensed under basic conditions.<ref>{{cite journal | vauthors = Asaki T, Kuwano K, Morrison K, Gatfield J, Hamamoto T, Clozel M | title = Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension | journal = Journal of Medicinal Chemistry | volume = 58 | issue = 18 | pages = 7128–7137 | date = September 2015 | pmid = 26291199 | doi = 10.1021/acs.jmedchem.5b00698 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Flick AC, Ding HX, Leverett CA, Kyne RE, Liu KK, Fink SJ, O'Donnell CJ | title = Synthetic Approaches to the New Drugs Approved During 2015 | journal = Journal of Medicinal Chemistry | volume = 60 | issue = 15 | pages = 6480–6515 | date = August 2017 | pmid = 28421763 | doi = 10.1021/acs.jmedchem.7b00010 | doi-access = free }}</ref> |
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{{cite journal|url=http://www.nejm.org/doi/full/10.1056/NEJMoa1009744 |
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|title=Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease |
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|journal=New England Journal of Medicine (published online) |
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|author=Cannon, Christopher, S. Shah et al |
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|date=November 17, 2010 |
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|doi=10.1056/NEJMoa1009744 |
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}}</ref> |
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==History== |
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Cardiologist ] described DEFINE as a medium-sized safety trial intended to find out "whether anacetrapib would show the same increase in adverse cardiovascular events that was seen with torcetrapib." Fortunately, anacetrapib did not. In his opinion the DEFINE study was too small to show a clear benefit, but the trends in the major adverse cardiovascular events were going in the right direction.<ref>{{cite web | title=DEFINE at AHA | url=http://www.theheart.org/article/1151979.do | title=DEFINE: Large effects on LDL and HDL cholesterol with CETP inhibitor anacetrapib|author=O'Riordan, Michael|publisher = theheart.org |
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The U.S. ] (FDA) granted selexipag ] designation for pulmonary arterial hypertension<ref>{{cite web | title=Selexipag Orphan Drug Designations and Approvals | website=U.S. ] (FDA) | date=1 January 2013 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=304810 | access-date=27 August 2023 | archive-date=28 August 2023 | archive-url=https://web.archive.org/web/20230828040623/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=304810 | url-status=live }}</ref> and for the treatment of chronic thromboembolic pulmonary hypertension.<ref>{{cite web | title=Selexipag Orphan Drug Designations and Approvals | website=U.S. ] (FDA) | date=1 January 2013 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=652018 | access-date=27 August 2023 | archive-date=28 August 2023 | archive-url=https://web.archive.org/web/20230828040504/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=652018 | url-status=live }}</ref> It was approved by the FDA in December 2015.<ref name="Uptravi FDA label" /><ref>{{cite web | title=Uptravi Tablets | website=U.S. ] (FDA) | date=28 January 2016 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207947Orig1s000TOC.cfm | access-date=27 August 2023 | archive-date=28 August 2023 | archive-url=https://web.archive.org/web/20230828034618/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207947Orig1s000TOC.cfm | url-status=live }}</ref> |
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|date=November 17, 2010}}</ref> |
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In the European Union, the drug was approved in May 2016.<ref name="Uptravi EPAR" /><ref name="EMA">{{cite web|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003774/human_med_001970.jsp&mid=WC0b01ac058001d124|title=Uptravi: Authorisation details|publisher=]|date=2016-05-12|access-date=8 June 2017|archive-date=20 June 2018|archive-url=https://web.archive.org/web/20180620153723/http://www.ema.europa.eu/ema//index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F003774%2Fhuman_med_001970.jsp&mid=WC0b01ac058001d124|url-status=live}}</ref> |
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Two year follow up due to complete by December 2012. |
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== Society and culture == |
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==See also== |
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=== Economics === |
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*], another CETP inhibitor, which was developed by ] but caused unacceptable increases in blood pressure and had net cardiovascular detriment. |
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The expected price for the drug in the US is $160,000 to $170,000 per patient before ]s.<ref>{{Cite news|title = Actelion sees Uptravi price of $160,000-170,000/patient|url = https://www.reuters.com/article/us-actelion-pah-prices-idUSKBN0UJ1SQ20160105|newspaper = Reuters|date = 2016-01-05|access-date = 2016-01-06|archive-date = 1 November 2018|archive-url = https://web.archive.org/web/20181101035923/https://www.reuters.com/article/us-actelion-pah-prices-idUSKBN0UJ1SQ20160105|url-status = live}}</ref> |
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==References== |
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== References == |
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{{Reflist}} |
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{{reflist}} |
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== External links == |
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{{Lipid modifying agents}} |
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* {{ClinicalTrialsGov|NCT03187678|Safety Study of the Switch From Oral Selexipag to Intravenous Selexipag in Subjects With Stable Pulmonary Arterial Hypertension}} |
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{{PAH rx}} |
|
] |
|
|
|
{{Prostanoidergics}} |
|
] |
|
|
|
{{Portal bar | Medicine}} |
|
] |
|
|
] |
|
|
|
|
|
|
{{cardiovascular-drug-stub}} |
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |