| 词条 | Olaparib |
| 释义 |
| Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 462264805 | IUPAC_name = 4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl) -4-fluorophenyl]methyl(2H)phthalazin-1-one | image = Olaparib.svg | tradename = Lynparza | pregnancy_AU = | pregnancy_US = | pregnancy_category = | licence_EU = yes | legal_AU = | legal_CA = | legal_UK = | legal_US = Rx-only | routes_of_administration = Oral | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | IUPHAR_ligand = 7519 | CAS_number_Ref = {{cascite|changed|??}} | CAS_number = 763113-22-0 | ATC_prefix = L01 | ATC_suffix = XX46 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 521686 | PubChem = 23725625 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | UNII_Ref = {{fdacite|correct|FDA}} | UNII = WOH1JD9AR8 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 23343272 | ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI = 83766 | KEGG = D09730 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C24H23FN4O3/c25-20-8-5-15(14-21-17-3-1-2-4-18(17)22(30)27-26-21)13-19(20)24(32)29-11-9-28(10-12-29)23(31)16-6-7-16/h1-5,8,13,16H,6-7,9-12,14H2,(H,27,30) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = FDLYAMZZIXQODN-UHFFFAOYSA-N | C=24 | H=23 | F=1 | N=4 | O=3 | molecular_weight = 435.08 g/mol | smiles = c4cccc2c4c(n[nH]c2=O)Cc(ccc1F)cc1C(=O)N3CCN(CC3)C(=O)C5CC5 }}Olaparib (AZD-2281, MK-7339 trade name Lynparza) is an FDA-approved targeted therapy for cancer. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.[1] In December 2014, olaparib was approved for use as a single agent by the EMA and the FDA.[2][3][4] The FDA approval is for germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy.[3] In January 2018, olaparib became the first PARP inhibitor to be approved by the FDA for gBRCAm metastatic breast cancer. It was developed in collaboration between AstraZeneca and Merck & Co.[5] Mechanism of actionOlaparib acts as an inhibitor of the enzyme poly ADP ribose polymerase (PARP), and is termed a PARP inhibitor. BRCA1/2 mutations may be genetically predisposed to development of some forms of cancer, and may be resistant to other forms of cancer treatment. However, these cancers sometimes have a unique vulnerability, as the cancer cells have increased reliance on PARP to repair their DNA and enable them to continue dividing. This means that drugs which selectively inhibit PARP may be of benefit if the cancers are susceptible to this treatment.[6][7] Approvals and indicationsIn December 2014, the FDA[3][4] and the EMA[2] approved olaparib as monotherapy. The FDA approval is in germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy.[3][8] The EMA public assessment report, which utilized the same phase II trial data, made reference to both "high grade serous ovarian cancers" and to the use of olaparib "not later than 8 weeks after a course of platinum-based medicines, when the tumour was diminishing in size or had completely disappeared".[2] In breast cancer, olaparib is approved for gBRCAm HER2-negative metastatic breast cancer patients who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. If patients have hormone receptor positive cancer, they should have received endocrine therapy where appropriate.[9] This approval was based on the OlympiAD randomised phase III trial, which showed a progression-free survival benefit for patients treated with olaparib compared to conventional chemotherapy [10][11] Side effectsSide effects include gastrointestinal effects such as nausea, vomiting, and loss of appetite; fatigue; muscle and joint pain; and low blood counts such as anemia, with occasional leukemia.[3] Somnolence was sometimes seen in clinical trials which used doses higher than the approved schedule.[1] References1. ^1 {{cite journal | vauthors = Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS | title = Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers | journal = The New England Journal of Medicine | volume = 361 | issue = 2 | pages = 123–34 | date = July 2009 | pmid = 19553641 | doi = 10.1056/NEJMoa0900212 | url = http://content.nejm.org/cgi/pmidlookup?view=short&pmid=19553641&promo=ONFLNS19 }} {{Chemotherapeutic agents}}2. ^1 2 {{cite web |url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/003726/WC500180153.pdf |title=Summary |website=ema.europa.eu}} 3. ^1 2 3 4 Olaparib (Lynparza) package insert at FDA.gov 4. ^1 {{cite web |url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427554.htm |title=Summary|website=fda.gov}} 5. ^{{Cite web|url=https://www.cancer.gov/news-events/cancer-currents-blog/2018/ovarian-cancer-olaparib-maintenance-therapy|title=National Cancer Institute - Olaparib after Initial Treatment Delays Ovarian Cancer Progression|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}} 6. ^{{cite web|url=http://www.emea.europa.eu/pdfs/human/comp/opinion/51078707en.pdf|title=Olaparib for the treatment of ovarian cancer.|website=europa.eu}} 7. ^{{cite journal | vauthors = Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM, Matthews IT, Moore S, O'Connor MJ, Smith GC, Martin NM | title = 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1 | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 20 | pages = 6581–91 | date = October 2008 | pmid = 18800822 | doi = 10.1021/jm8001263 }} 8. ^{{cite journal | vauthors = Wiggans AJ, Cass GK, Bryant A, Lawrie TA, Morrison J | title = Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD007929 | date = May 2015 | pmid = 25991068 | doi = 10.1002/14651858.CD007929.pub3 }} 9. ^{{cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdf|title=Olaparib (Lynparza) package insert (January 2018)|website=fda.gov}} 10. ^{{cite journal | vauthors = Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P | title = Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation | journal = The New England Journal of Medicine | volume = 377 | issue = 6 | pages = 523–533 | date = August 2017 | pmid = 28578601 | pmc = | doi = 10.1056/NEJMoa1706450 | url = https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28578601 }} 11. ^{{cite web|url=https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm592357.htm|title=Approved Drugs - FDA approves olaparib for germline BRCA-mutated metastatic breast cancer|first=Center for Drug Evaluation and|last=Research|website=www.fda.gov}} 7 : Carboxamides|Fluoroarenes|Lactams|PARP inhibitors|Phthalazines|Piperazines|AstraZeneca |
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