4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1
4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1
复制标题
DOI：
10.1021/jm8001263
复制
发表时间：
2008-10-23
影响因子：
7.3
通讯作者：
Martin, Niall M. B.
中科院分区：
文献类型：
--
作者：
Menear, Keith A.;Adcock, Claire;Martin, Niall M. B.
聚（ADP-核糖）聚合酶激活是细胞对代谢、化学或电离辐射引起的 DNA 损伤的立即反应，代表了癌症治疗的新靶点。在这篇文章中，我们公开了一系列新型取代的 4-benzyl-2H-phaazin-1-ones，它们对 PARP-1 和 PARP-2 具有高抑制酶和细胞效力。该系列的优化化合物还在 SW620 结直肠癌异种移植模型中表现出良好的药代动力学特征、口服生物利用度和体内活性。 4-[3-(4-环丙烷羰基哌嗪-1-羰基)-4-氟苄基]-2H-酞嗪-1-one (KU-0059436, AZD2281) 47 是 PARP-1 和 PARP-2 的一位数纳摩尔抑制剂，对 BRCA1 缺陷型乳腺癌细胞系显示出独立活性。化合物 47 目前正在进行临床开发，用于治疗 BRCA1 和 BRCA2 缺陷型癌症。
Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.