WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 406655
CAS#: 1527473-33-1
Description: 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.
MedKoo Cat#: 406655
Name: PF06447475
CAS#: 1527473-33-1
Chemical Formula: C17H15N5O
Exact Mass: 305.12766
Molecular Weight: 305.33
Elemental Analysis: C, 66.87; H, 4.95; N, 22.94; O, 5.24
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
| 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 | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 30.0 | 98.3 |
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.
| 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: Henderson JL, Kormos BL, Hayward MM, Coffman KJ, Jasti J, Kurumbail RG, Wager TT, Verhoest PR, Noell GS, Chen Y, Needle E, Berger Z, Steyn SJ, Houle C, Hirst WD, Galatsis P. 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. doi: 10.1021/jm5014055. Epub 2014 Nov 17. PubMed PMID: 25353650.
