Synonym
PF-06454589; PF 06454589; PF06454589.
IUPAC/Chemical Name
4-[5-(1-methylpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]morpholine
InChi Key
VNWKCLDQBNSJJO-UHFFFAOYSA-N
InChi Code
InChI=1S/C14H16N6O/c1-19-8-10(6-18-19)11-7-15-13-12(11)14(17-9-16-13)20-2-4-21-5-3-20/h6-9H,2-5H2,1H3,(H,15,16,17)
SMILES Code
CN1N=CC(C2=CNC3=NC=NC(N4CCOCC4)=C32)=C1
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
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 highly potent, selective and brain penetrant LRRK2 inhibitor with an IC50 of 3 nM.
In vitro activity:
To compare these molecules directly, this study found that both MLi-2 and PF-06447475 inhibited LRRK2 peptide phosphorylation with similar IC50 values of 1.1 ± 0.2 and 3.5 ± 1.1 nm, respectively (Fig. 5B), demonstrating exceptional potency for both molecules. A LRRK2 peptide phosphorylation assay in the presence of 1.1 nm of MLi-2 or 3.5 nm of PF-06447475 demonstrated that both inhibitors increased the Km-ATP (149.9 ± 9.7, 421.4 ± 18.7, and 272.3 ± 14.3 μm in the presence of DMSO, MLi-2, or PF-06447475, respectively) while leaving the Vmax unchanged (1.97 ± 0.03 min), suggesting a near-perfect ATP-competitive inhibitory profile that is comparable between the two molecules (Fig. 5C). These results show that MLi-2 and PF-06447475 inhibit LRRK2 in a similar, ATP-competitive manner and with similar potencies and have nanomolar inhibition profiles at physiological ATP concentrations.
Reference: J Neurosci. 2016 Jul 13;36(28):7415-27. https://pubmed.ncbi.nlm.nih.gov/27413152/
In vivo activity:
To better understand the therapeutic potential of LRRK2 kinase inhibition in PD, this study evaluated the tolerability and efficacy of a LRRK2 kinase inhibitor, PF-06447475, in preventing α-synuclein-induced neurodegeneration in rats. Rats were treated with PF-06447475 or a control compound for 4 weeks post-viral transduction. This study found that rats expressing G2019S-LRRK2 have exacerbated dopaminergic neurodegeneration and inflammation in response to the overexpression of α-synuclein. Both neurodegeneration and neuroinflammation associated with G2019S-LRRK2 expression were mitigated by LRRK2 kinase inhibition. Furthermore, PF-06447475 provided neuroprotection in wild-type rats. This study could not detect adverse pathological indications in the lung, kidney, or liver of rats treated with PF-06447475.
Reference: J Biol Chem. 2015 Aug 7;290(32):19433-44. https://pubmed.ncbi.nlm.nih.gov/26078453/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
60.5 |
212.79 |
|
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
284.32
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. 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. PMID: 27413152; PMCID: PMC4945663.
2. 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.
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.
In vitro protocol:
1. 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. PMID: 27413152; PMCID: PMC4945663.
In vivo protocol:
1. 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.
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.
Henderson, J. L., Kormos, B. L., Hayward, M. M., Coffman, K. J., Jasti, J., Kurumbail, R. G., ... & Galatsis, P. (2015). Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7 H-pyrrolo [2, 3-d] pyrimidin-5-yl] benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. Journal of medicinal chemistry, 58(1), 419-432.
