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MedKoo Cat#: 406655 | Name: PF06447475
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

PF06447475 is a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD.

Chemical Structure

PF06447475
PF06447475
CAS#1527473-33-1

Theoretical Analysis

MedKoo Cat#: 406655

Name: PF06447475

CAS#: 1527473-33-1

Chemical Formula: C17H15N5O

Exact Mass: 305.1277

Molecular Weight: 305.33

Elemental Analysis: C, 66.87; H, 4.95; N, 22.94; O, 5.24

Price and Availability

Size Price Availability Quantity
10mg USD 90.00 Ready to ship
25mg USD 150.00 Ready to ship
50mg USD 250.00 Ready to ship
100mg USD 450.00 Ready to ship
200mg USD 750.00 Ready to ship
1g USD 2,950.00 Ready to ship
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Related CAS #
No Data
Synonym
PF06447475; PF-06447475; PF 06447475; PF6447475; PF-6447475; PF 6447475.
IUPAC/Chemical Name
3-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile
InChi Key
BHTWDJBVZQBRKP-UHFFFAOYSA-N
InChi Code
InChI=1S/C17H15N5O/c18-9-12-2-1-3-13(8-12)14-10-19-16-15(14)17(21-11-20-16)22-4-6-23-7-5-22/h1-3,8,10-11H,4-7H2,(H,19,20,21)
SMILES Code
N#CC1=CC=CC(C2=CNC3=NC=NC(N4CCOCC4)=C32)=C1
Appearance
White to off-white solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
        
Biological target:
PF-06447475 is a brain penetrant LRRK2 inhibitor with an IC50 of 3 nM.
In vitro activity:
This study evaluated the effect of PF-475 (PF-06447475) on NCL exposed to ROT. As shown in Fig. 5, ROT significantly increased p-(S935)-LRRK2 levels compared to untreated NLCs (Fig. 5 a, b). In contrast, cells incubated with PF-475 alone (0.5, 1, 3 µM) or in the presence of ROT significantly reduced (S935)-LRRK2 kinase phosphorylation to control values (Fig. 5a–b). The total LRRK2 was affected neither by ROT nor by inhibitor alone (Fig. 5c). Similar results were obtained by IF analysis (Fig. 5d–g). Reference: Neurochem Res. 2016 Oct;41(10):2675-2692. https://pubmed.ncbi.nlm.nih.gov/27394417/
In vivo activity:
To determine whether LRRK2 played a role in regulating the p38 MAPK pathway and its downstream molecule Drosha, western blot analyses of the peri-injury cortex were performed, and changes in the protein levels of p-p38 and Drosha were quantified following LRRK2 inhibition or overexpression at 12 h after TBI or sham surgery. Results demonstrated that LRRK2 inhibitor PF-475 (PF06447475) decreased p-p38 expression in a dose-dependent manner (F(5,30) = 27.13, P < 0.05, Figures 6A,C), whereas LRRK2 overexpression significantly enhanced the p-p38 level. Conversely, the expression of Drosha, which was upregulated with the PF-475 treatment (F(5,30) = 21.58, P < 0.05, Figures 6B,D) and greatly downregulated in the LRRK2 overexpression group (P < 0.05), showed an opposite trend to that of p-p38. Reference: Front Cell Neurosci. 2018; 12: 51. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837969/
Solvent mg/mL mM
Solubility
DMSO 30.0 98.30
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 305.33 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
1. 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. 2. Henry AG, Aghamohammadzadeh S, Samaroo H, Chen Y, Mou K, Needle E, Hirst WD. Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression. Hum Mol Genet. 2015 Nov 1;24(21):6013-28. doi: 10.1093/hmg/ddv314. Epub 2015 Aug 6. PMID: 26251043. 3. Rui Q, Ni H, Gao F, Dang B, Li D, Gao R, Chen G. LRRK2 Contributes to Secondary Brain Injury Through a p38/Drosha Signaling Pathway After Traumatic Brain Injury in Rats. Front Cell Neurosci. 2018 Mar 1;12:51. doi: 10.3389/fncel.2018.00051. PMID: 29545743; PMCID: PMC5837969. 4. 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.
In vitro protocol:
1. 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. 2. Henry AG, Aghamohammadzadeh S, Samaroo H, Chen Y, Mou K, Needle E, Hirst WD. Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression. Hum Mol Genet. 2015 Nov 1;24(21):6013-28. doi: 10.1093/hmg/ddv314. Epub 2015 Aug 6. PMID: 26251043.
In vivo protocol:
1. Rui Q, Ni H, Gao F, Dang B, Li D, Gao R, Chen G. LRRK2 Contributes to Secondary Brain Injury Through a p38/Drosha Signaling Pathway After Traumatic Brain Injury in Rats. Front Cell Neurosci. 2018 Mar 1;12:51. doi: 10.3389/fncel.2018.00051. PMID: 29545743; PMCID: PMC5837969. 2. 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.
1: Quintero-Espinosa DA, Jimenez-Del-Rio M, Velez-Pardo C. LRRK2 Kinase Inhibitor PF-06447475 Protects Drosophila melanogaster against Paraquat-Induced Locomotor Impairment, Life Span Reduction, and Oxidative Stress. Neurochem Res. 2024 Sep;49(9):2440-2452. doi: 10.1007/s11064-024-04141-9. Epub 2024 Jun 7. PMID: 38847910; PMCID: PMC11310290. 2: Giraldo-Berrio D, Mendivil-Perez M, Velez-Pardo C, Jimenez-Del-Rio M. Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson's Disease Dementia (PDD). Neurotox Res. 2024 Jun 6;42(3):28. doi: 10.1007/s12640-024-00705-3. PMID: 38842585; PMCID: PMC11156752. 3: Naskar A, Roy RK, Srivastava D, Patra N. Decoding Inhibitor Egression from Wild-Type and G2019S Mutant LRRK2 Kinase: Insights into Unbinding Mechanisms for Precision Drug Design in Parkinson's Disease. J Phys Chem B. 2024 Jul 18;128(28):6657-6669. doi: 10.1021/acs.jpcb.4c00335. Epub 2024 Jun 1. PMID: 38822803. 4: Zheng Z, Zhang S, Liu X, Wang X, Xue C, Wu X, Zhang X, Xu X, Liu Z, Yao L, Lu G. LRRK2 regulates ferroptosis through the system Xc-GSH-GPX4 pathway in the neuroinflammatory mechanism of Parkinson's disease. J Cell Physiol. 2024 May;239(5):e31250. doi: 10.1002/jcp.31250. Epub 2024 Mar 13. PMID: 38477420. 5: Rak M, Menge A, Tesch R, Berger LM, Balourdas DI, Shevchenko E, Krämer A, Elson L, Berger BT, Abdi I, Wahl LM, Poso A, Kaiser A, Hanke T, Kronenberger T, Joerger AC, Müller S, Knapp S. Development of Selective Pyrido[2,3-d]pyrimidin-7(8H)-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors. J Med Chem. 2024 Mar 14;67(5):3813-3842. doi: 10.1021/acs.jmedchem.3c02217. Epub 2024 Feb 29. PMID: 38422480. 6: Chen Z, Chen J, Mori W, Yi Y, Rong J, Li Y, Leon ERC, Shao T, Song Z, Yamasaki T, Ishii H, Zhang Y, Kokufuta T, Hu K, Xie L, Josephson L, Van R, Shao Y, Factor S, Zhang MR, Liang SH. Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2). J Med Chem. 2024 Feb 22;67(4):2559-2569. doi: 10.1021/acs.jmedchem.3c01687. Epub 2024 Feb 2. PMID: 38305157; PMCID: PMC10895652. 7: Quintero-Espinosa DA, Velez-Pardo C, Jimenez-Del-Rio M. High Yield of Functional Dopamine-like Neurons Obtained in NeuroForsk 2.0 Medium to Study Acute and Chronic Rotenone Effects on Oxidative Stress, Autophagy, and Apoptosis. Int J Mol Sci. 2023 Oct 30;24(21):15744. doi: 10.3390/ijms242115744. PMID: 37958728; PMCID: PMC10647258. 8: Naskar A, Bhanja KK, Roy RK, Patra N. Structural insight into G2019S mutated LRRK2 kinase and brain-penetrant type I inhibitor complex: a molecular dynamics approach. J Biomol Struct Dyn. 2023 Sep 13:1-21. doi: 10.1080/07391102.2023.2255675. Epub ahead of print. PMID: 37702159. 9: Kania E, Long JS, McEwan DG, Welkenhuyzen K, La Rovere R, Luyten T, Halpin J, Lobbestael E, Baekelandt V, Bultynck G, Ryan KM, Parys JB. LRRK2 phosphorylation status and kinase activity regulate (macro)autophagy in a Rab8a/Rab10-dependent manner. Cell Death Dis. 2023 Jul 15;14(7):436. doi: 10.1038/s41419-023-05964-0. PMID: 37454104; PMCID: PMC10349885. 10: Mutti V, Carini G, Filippini A, Castrezzati S, Giugno L, Gennarelli M, Russo I. LRRK2 Kinase Inhibition Attenuates Neuroinflammation and Cytotoxicity in Animal Models of Alzheimer's and Parkinson's Disease-Related Neuroinflammation. Cells. 2023 Jul 6;12(13):1799. doi: 10.3390/cells12131799. PMID: 37443833; PMCID: PMC10340668. 11: Filippone A, Cucinotta L, Bova V, Lanza M, Casili G, Paterniti I, Campolo M, Cuzzocrea S, Esposito E. Inhibition of LRRK2 Attenuates Depression-Related Symptoms in Mice with Moderate Traumatic Brain Injury. Cells. 2023 Mar 29;12(7):1040. doi: 10.3390/cells12071040. PMID: 37048114; PMCID: PMC10093681. 12: Filippone A, Mannino D, Cucinotta L, Paterniti I, Esposito E, Campolo M. LRRK2 Inhibition by PF06447475 Antagonist Modulates Early Neuronal Damage after Spinal Cord Trauma. Antioxidants (Basel). 2022 Aug 23;11(9):1634. doi: 10.3390/antiox11091634. PMID: 36139708; PMCID: PMC9495377. 13: Li J, Wu M, Gong Y, Tang J, Shen J, Xu L, Dang B, Chen G. Inhibition of LRRK2-Rab10 Pathway Improves Secondary Brain Injury After Surgical Brain Injury in Rats. Front Surg. 2022 Jan 5;8:749310. doi: 10.3389/fsurg.2021.749310. PMID: 35071308; PMCID: PMC8766807. 14: Novello S, Mercatelli D, Albanese F, Domenicale C, Brugnoli A, D'Aversa E, Vantaggiato S, Dovero S, Murtaj V, Presotto L, Borgatti M, Shimshek DR, Bezard E, Moresco RM, Belloli S, Morari M. In vivo susceptibility to energy failure parkinsonism and LRRK2 kinase activity. Neurobiol Dis. 2022 Jan;162:105579. doi: 10.1016/j.nbd.2021.105579. Epub 2021 Dec 3. PMID: 34871735. 15: Chen X, Zhang Q, Zhang Y, Fang J, Jiang D, Mou Z, Liu H, Su R, Wang C, He F, Chen X, Xie F, Pan X, Li Z. 18F-Labelled pyrrolopyrimidines reveal brain leucine-rich repeat kinase 2 expression implicated in Parkinson's disease. Eur J Med Chem. 2021 Mar 15;214:113245. doi: 10.1016/j.ejmech.2021.113245. Epub 2021 Feb 4. PMID: 33582389. 16: Wallings R, Connor-Robson N, Wade-Martins R. LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function. Hum Mol Genet. 2019 Aug 15;28(16):2696-2710. doi: 10.1093/hmg/ddz088. PMID: 31039583; PMCID: PMC6687951. 17: Rui Q, Ni H, Gao F, Dang B, Li D, Gao R, Chen G. LRRK2 Contributes to Secondary Brain Injury Through a p38/Drosha Signaling Pathway After Traumatic Brain Injury in Rats. Front Cell Neurosci. 2018 Mar 1;12:51. doi: 10.3389/fncel.2018.00051. PMID: 29545743; PMCID: PMC5837969. 18: Malik N, Gifford AN, Sandell J, Tuchman D, Ding YS. Synthesis and In Vitro and In Vivo Evaluation of [3H]LRRK2-IN-1 as a Novel Radioligand for LRRK2. Mol Imaging Biol. 2017 Dec;19(6):837-845. doi: 10.1007/s11307-017-1070-1. Erratum in: Mol Imaging Biol. 2017 Dec;19(6):846. doi: 10.1007/s11307-017-1086-6. PMID: 28289968; PMCID: PMC5597475. 19: Volpicelli-Daley LA, Abdelmotilib H, Liu Z, Stoyka L, Daher JP, Milnerwood AJ, Unni VK, Hirst WD, Yue Z, Zhao HT, Fraser K, Kennedy RE, West AB. G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons. J Neurosci. 2016 Jul 13;36(28):7415-27. doi: 10.1523/JNEUROSCI.3642-15.2016. Erratum in: J Neurosci. 2022 Jan 26;42(4):718. doi: 10.1523/JNEUROSCI.2468-21.2021. PMID: 27413152; PMCID: PMC4945663. 20: 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.