Development of substituted 6-(4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells.

Ferrigno F; Branca D; Kinzel

首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Development of substituted 6-(4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells.

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Development of substituted 6-(4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells.

机译：作为有效的聚（ADP-核糖）聚合酶-1（PARP-1）的取代的6-（4-氟-3-（哌嗪-1-基羰基）苄基）-4,5-二甲基哒嗪-3（2H）-的开发在BRCA缺陷细胞中有活性的抑制剂。

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We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.

机译：我们在6- [4-氟-3-（取代的）苄基] -4,5-二甲基哒嗪-3（2H）-一个系列中描述了广泛的SAR研究，该研究导致了有效的PARP-1抑制剂的鉴定，在低纳摩尔范围内抑制BRCA-1缺陷癌细胞的增殖，并显示出比BRCA野生型对应物高100倍以上的选择性。该系列化合物没有hERG通道活性，CYP抑制和诱导作用。几种类似物在大鼠和人的肝微粒体中稳定，并显示出中等的大鼠清除率，其中母体尿排泄是消除的主要途径。

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《Bioorganic and Medicinal Chemistry Letters》 |2010年第3期|共6页
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Ferrigno F; Branca D; Kinzel;
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1. Development of substituted 6-(4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells. [J] . Ferrigno F, Branca D, Kinzel Bioorganic and Medicinal Chemistry Letters . 2010,第3期

机译：作为有效的聚（ADP-核糖）聚合酶-1（PARP-1）的取代的6-（4-氟-3-（哌嗪-1-基羰基）苄基）-4,5-二甲基哒嗪-3（2H）-的开发在BRCA缺陷细胞中有活性的抑制剂。
2. Identification of substituted pyrazolo(1,5-a)quinazolin-5(4H)-one as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. [J] . Orvieto F, Branca D, Giomini C Bioorganic and Medicinal Chemistry Letters . 2009,第15期

机译：确定取代的吡唑并（1,5-a）喹唑啉-5（4H）-一为有效的聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂。
3. Identification of substituted pyrazolo(1,5-a)quinazolin-5(4H)-one as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. [J] . Orvieto F, Branca D, Giomini C Bioorganic and Medicinal Chemistry Letters . 2009,第15期

机译：确定取代的吡唑并（1,5-a）喹唑啉-5（4H）-一为有效的聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂。
4. Design, Synthesis, and Cytoprotective Effect of 2-Aminothiazole Analogues as Potent Poly(ADP-Ribose) Polymerase-1 Inhibitors [C] . Wen-Ting Zhang, Gang-Ying Chen, Yi-Jing Zhu, ICMSI;International conference of molecular simulations and applied informatics technologies . 2010

机译：2-氨基噻唑类似物作为强力聚（ADP-核糖）聚合酶-1抑制剂的设计，合成和细胞保护作用
5. Evaluation of selected antioxidants and inhibitors of poly (ADP-ribose) polymerase-1 (PARP-1) as protective agents against mustard toxicity in vitro. [D] . Pino, Maria A. 2010

机译：评价选定的抗氧化剂和聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂作为体外抗芥子油毒性的保护剂。
6. Synthesis 18F radiolabeling and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography [O] . Dong Zhou, Wenhua Chu, Jinbin Xu, -1

机译：合成18F放射性标记和聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂的评估用于使用正电子发射断层扫描术对PARP-1进行体内成像
7. Synthesis, 18F radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography [O] . Dong Zhou, Wenhua Chu, Jinbin Xu, 2014

机译：合成，18F放射性标记和评价聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂，用于使用正电子发射断层扫描的PARP-1体内成像
8. Treatment of BRCA1/2 Hereditary Breast Cancer and Sporadic Breast Cancer with Poly(ADP-ribose) PARP-1 Inhibitors and Chemotherapy [R] . DeSoto, J. A. 2008

机译：聚（aDp-核糖）paRp-1抑制剂和化疗治疗BRCa1 / 2遗传性乳腺癌和散发性乳腺癌

Development of substituted 6-(4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells.

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