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Synthesis of PAPP Inhibitor Olaparib (Lynparza), AstraZeneca’s Ovarian Cancer Drug
2015-05-10 07:14:08

Synthesis of Ovarian Cancer Drug Olaparib_Lynparza_PAPP Inhibitor_AstraZeneca 阿斯利康卵巢癌試驗藥物奧拉帕尼(Olaparib,オラパリブ)的化學合成

Trade Name:Lynparza
Generic Name: Olaparib, オラパリブ
Synonym: AZD2281; KU-0059436
Chinese Name: 奧拉帕尼
Chemical Name:4-[(3-[(4-cyclopropylcarbonyl)piperazin-4-yl]carbonyl)-4-fluorophenyl]methyl(2H) phthalazin-1-one
CAS Number:763113-22-0
Mechanism of Action:Poly(ADP-ribose) polymerase inhibitors
Indication: Ovarian cancer
Date of Approval:December 19, 2014 (US), December 18, 2014 (EU)
Originator:KuDOS Pharmaceuticals
Developer: AstraZeneca


米食品醫薬品局(FDA)は12月19日、英アストラゼネカ(AZ)のPARP(ポリADP-リボース合成酵素)阻害剤Lynparza(オラパリ ブ)をBRCA遺伝子変異陽性の進行卵巣がんの適応で承認した。また、併せて、同剤のコンパニオン?ダイアグノスティクスである BRACAnalysisCDxも承認した。オラパリブの適応は、BRCA遺伝子欠損のある前治療歴を持つ進行卵巣がんである。BRCA遺伝子は、損傷さ れたDNAの修復に関與し、通常、腫瘍の成長を抑制する。BRCA遺伝子欠損をもたらす同遺伝子変異の女性は卵巣がんになりやすく、卵巣がん患者の全體の 10%-15%は遺伝性のBRCA変異に関與しているとみられる。




Jonathan Ledermann,Philipp Harter,Charlie Gourley,Michael Friedlander et al. Lancet Oncol. 2014;15:852-861

Bella Kaufman,Ronnie Shapira-Frommer,Rita K. Schmutzler,M. William Audeh,Susan M. Domchek et al.,Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation ,J Clin Oncol. Published online November 3, 2014 (JCO.2014.56.2728 ).

Martin, Niall Morrison Barr et al,Preparation of phthalazinones as PARP inhibitors,PCT Int. Appl., WO2004080976

Menear, Keith Allan et al,Preparation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one and its crystal forms as PARP-1 inhibitors,PCT Int. Appl., WO2008047082

Menear, Keith A. et al.4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1,Journal of Medicinal Chemistry, 51(20), 6581-6591; 2008

Lou, Xi-yu; Yang, Xuan; Ding, Yi-li; Wang, Jian-jun; Yan, Qing-yan; Huang, Xian-gui; Guo, Yang-hui; Wang, Xiang-jing; Xiang, Wen-sheng, Synthesis of Olaparib derivatives and their antitumor activities, Chemical Research in Chinese Universities (2013), 29(2), 231-235.

The Phase II study for Olaparib was published in N Engl J Med 2012; 366:1382-1392 .by Jonathan Ledermann et al, titled “Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer”

Jose Lutzky, A phase 1 study of MEDI4736, an anti–PD-L1 antibody, in patients with advanced solid tumors. American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, June 3, 2014, Abstract 3001

Neil Howard Segal, Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody, American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, June 3, 2014, Abstract 3002

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