FMS/KIT双重抑制剂(PLX647) | 873786-09-5

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: FMS/KIT双重抑制剂(PLX647)
• 中文别名: 化合物PLX647；PLX647抑制剂
• 英文名称: PLX647
• 英文别名: [5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine；5-(1h-Pyrrolo[2,3-B]pyridin-3-Ylmethyl)-N-[4-(Trifluoromethyl)benzyl]pyridin-2-Amine；5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-N-[[4-(trifluoromethyl)phenyl]methyl]pyridin-2-amine
• CAS: 873786-09-5
• 化学式: C₂₁H₁₇F₃N₄
• 分子量: 382.388
• InChiKey: NODCQQSEMCESEC-UHFFFAOYSA-N

物化性质

• 密度：
  1.358±0.06 g/cm3(Predicted)
• 溶解度：
  在DMSO中的溶解度为20mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  53.6
• 氢给体数：
  2
• 氢受体数：
  6

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S36/37/39
• 危险类别码：
  R36/37/38
• WGK Germany：
  3

制备方法与用途

生物活性

PLX647 是一种高度特异性的，具有口服活性的 FMS 和 KIT 双激酶抑制剂，IC50 分别为 28 和 16 nM。PLX647 (1 μM) 在 400 个激酶组中显示出对 FMS 和 KIT 有选择性，但 FLT3 和 KDR 除外 (IC50=91 和 130 nM)。

体外研究

In vitro, PLX647 potently inhibits proliferation of BCR-FMS cells, with an IC ₅₀ of 92 nM. A corresponding Ba/F3 cell line expressing BCR-KIT is also quite sensitive to PLX647, with an IC ₅₀ of 180 nM. PLX647 also inhibits endogenous FMS and KIT, as demonstrated by inhibition of the ligand-dependent cell lines M-NFS-60 (IC ₅₀ =380 nM) and M-07e (IC ₅₀ =230 nM), which express FMS and KIT, respectively.
PLX647 potently inhibits the growth of FLT3–ITD-expressing MV4-11 cells (IC ₅₀ =110 nM). PLX647 displayed minimal inhibition of the proliferation of Ba/F3 cells expressing BCR–KDR (IC ₅₀ =5 μM). PLX647 inhibits osteoclast differentiation with an IC ₅₀ of 0.17 μM.

体内研究

PLX647 (40 mg/kg; p.o.; twice daily for 7 days) reduces macrophage accumulation in UUO kidney and blood monocytes.
PLX647 (40 mg/kg; p.o.; male Swiss Webster mice) reduces LPS-induced TNF-α and IL-6 release.
PLX647 (20-80 mg/kg; p.o.; daily or twice daily from 27-41 days) shows effects on collagen-induced arthritis.
PLX647 (30 mg/kg) results in significant inhibition of TRAP5b immunostaining and bone osteolysis. PLX647 (30 mg/kg BID) is able to prevent bone damage by the tumor cells.

Animal Model:	Male C57BL/6 mice (mouse unilateral ureter obstruction model)
Dosage:	40 mg/kg
Administration:	P.o.; twice daily for 7 days
Result:	Resulted in reduction in the levels of F4/80+ macrophages by 77%.

Animal Model:	7-9 wk old Male DBA/1J mice (Mouse collagen-induced arthritis model)
Dosage:	20 mg/kg, 80 mg/kg
Administration:	P.o.; daily (20 mg/kg) from 27-41 days, twice daily (80 mg/kg) from 27-41 days
Result:	20 mg/kg PLX647 had no initial effect on the development of severe arthritis. However, starting on day 33, no further development of disease severity was recorded, and a 30% inhibition of the macroscopic signs of arthritis was evident in clinical score on day 41. Mice treated with 80 mg/kg BID PLX647 initially shows delayed development of severe arthritic signs. Starting on day 33, the signs of arthritis began to decrease in this treatment group, reaching a maximum reversal of 76% on day 41.

反应信息

• 作为产物：
  描述：

  (1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(4-trifluoromethylbenzylamino)pyridin-3-yl]methanol 在 三乙基硅烷 、 三氟乙酸 作用下， 反应 0.5h， 以62.8%的产率得到FMS/KIT双重抑制剂(PLX647)
  参考文献：
  名称：

  [EN] AZAINDOLES MODULATING C-KIT ACTIVITY AND USES THEREFOR
  [FR] COMPOSES MODULANT L'ACTIVITE DE C-KIT

  摘要：

  公开号：

  WO2006009755A3

文献信息

• Compounds modulating c-kit activity and uses therefor
  申请人：Ibrahim N. Prabha

  公开号：US20060058339A1

  公开（公告）日：2006-03-16

  Compounds with generic structure 5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-benzylpyridine-2-amine with activity toward the receptor protein tyrosine kinase c-kit, compositions useful for treatment c-kit-mediate diseases or conditions, and methods of use thereof are described.

  本文描述了具有通用结构5-((1H-吡咯并[2,3-b]吡啶-3-基)甲基)-N-苄基吡啶-2-胺的化合物，其具有对受体蛋白酪氨酸激酶c-kit的活性，适用于治疗c-kit介导疾病或病况的组合物，以及其使用方法。
• Compounds modulating c-kit activity
  申请人：Ibrahim N. Prabha

  公开号：US20060058340A1

  公开（公告）日：2006-03-16

  Compounds with 7-azaindole core structure with activity toward the receptor protein tyrosine kinase c-kit, compositions useful for treatment c-kit-mediate diseases or conditions, and methods of use thereof, are provided. Further provided are methods of c-kit ligand identification and design.

  本发明提供了具有对受体蛋白酪氨酸激酶c-kit活性的7-氮杂吲哚核心结构的化合物，以及用于治疗c-kit介导的疾病或病况的组合物和使用方法。此外，还提供了c-kit配体识别和设计的方法。
• Compounds modulating c-fms and/or c-kit activity and uses therefor
  申请人：Zhang Jiazhong

  公开号：US20090076046A1

  公开（公告）日：2009-03-19

  Compounds active on the receptor protein tyrosine kinases c-kit and/or c-fms are provided herewith. Also provided herewith are compositions useful for treatment of c-kit mediated diseases or conditions and/or c-fms-mediated diseases or conditions, and methods for the use thereof.

  提供了对受体蛋白酪氨酸激酶c-kit和/或c-fms活性的化合物。还提供了用于治疗c-kit介导的疾病或病状和/或c-fms介导的疾病或病状的组合物，以及使用它们的方法。
• Compounds modulating c-kit and c-fms activity and uses therefor
  申请人：Zhang Chao

  公开号：US20070032519A1

  公开（公告）日：2007-02-08

  Compounds active on the receptor protein tyrosine kinases c-kit and c-fms are provided herewith. Also provided herewith are compositions useful for treatment of c-kit mediated diseases or condition and c-fms-mediated diseases or condition, and methods for the use thereof.

  本文提供了对受体蛋白酪氨酸激酶c-kit和c-fms活性的化合物。本文还提供了用于治疗c-kit介导的疾病或病况以及c-fms介导的疾病或病况的组合物，以及其使用方法。
• Compounds Modulating C-Kit Activity
  申请人：Ibrahim Prabha N.

  公开号：US20090105297A1

  公开（公告）日：2009-04-23

  Compounds with 7-azaindole core structure with activity toward the receptor protein tyrosine kinase c-kit, compositions useful for treatment c-kit-mediate diseases or conditions, and methods of use thereof, are provided. Further provided are methods of c-kit ligand identification and design.

  提供了具有对受体蛋白酪氨酸激酶c-kit活性的7-氮杂吲哚核心结构的化合物，以及用于治疗c-kit介导的疾病或病症的组合物和使用方法。此外还提供了c-kit配体鉴定和设计的方法。