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PF-06447475

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Chemical Structure| 1527473-33-1 同义名 : -
CAS号 : 1527473-33-1
货号 : A125109
分子式 : C17H15N5O
纯度 : 99%+
分子量 : 305.334
MDL号 : MFCD28347838
存储条件：

粉末 Sealed in dry,Room Temperature

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 60 mg/mL(196.51 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • LRRK2

    LRRK2, IC50:3nM
描述 G2019S, the most prevalent Leucine rich repeat kinase 2 (LRRK2) mutation, may upregulate LRRK2 kinase activity and is the most common known genetic cause of Parkinson’s disease (PD), and thus LRRK2 is a highly promising therapeutic target for PD. PF-06447475 is a highly potent, brain penetrant and selective LRRK2 inhibitor with IC50 of 3 nM and 11 nM for Wild type LRRK2 and G2019S LRRK2 respectively. PF-06447475 at 30 mg/kg p.o. b.i.d. was applied to G2019S+ rats for 4 weeks, stereological estimations of the number of substantia nigra pars compacta (SNpc) TH neurons showed that an ~40% loss of cells occurred in the group of G2019S+ rats treated with the control compound while there was no significant loss of TH cells in the SNpc in G2019S+ rats treated with PF-06447475. A significant reduction in microgliosis and proinflammatory marker MHC-II expressed on myeloid cells but not neurons could be observed in G2019S+ rats treated with PF-06447475, compared with those treated with control drug[3]. PF-06447475 at 1 µM protected nerve-like differentiated cells against rotenone (ROT) induced noxious effect via blocking the p-(S935)-LRRK2 kinase phosphorylation, abolishing reactive oxygen species, and reversing all ROT-induced apoptosis signaling and oxidative stress associated markers to comparable control values[4].
作用机制 PF-06447475 inhibits LRRK2 by interacting with the pyrrolopyrimidine scaffold, a well-known two-point hinge binder in kinases.
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

3.28mL

0.66mL

0.33mL

16.38mL

3.28mL

1.64mL

32.75mL

6.55mL

3.28mL
参考文献

[1]Henderson JL, Kormos BL, et al. Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d] pyrimidin-5-yl] benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. J Med Chem. 2015 Jan 8;58(1):419-32.

[2]Daher JP, Abdelmotilib HA, et al. Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration. J Biol Chem. 2015 Aug 7;290(32):19433-44.

[3]Daher JP, Abdelmotilib HA, Hu X, Volpicelli-Daley LA, Moehle MS, Fraser KB, Needle E, Chen Y, Steyn SJ, Galatsis P, Hirst WD, West AB. Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration. J Biol Chem. 2015 Aug 7;290(32):19433-44. doi: 10.1074/jbc.M115.660001. Epub 2015 Jun 15. PMID: 26078453; PMCID: PMC4528108.

[4]Mendivil-Perez M, Velez-Pardo C, Jimenez-Del-Rio M. Neuroprotective Effect of the LRRK2 Kinase Inhibitor PF-06447475 in Human Nerve-Like Differentiated Cells Exposed to Oxidative Stress Stimuli: Implications for Parkinson's Disease. Neurochem Res. 2016 Oct;41(10):2675-2692. doi: 10.1007/s11064-016-1982-1. Epub 2016 Jul 9. PMID: 27394417.