PF-06454589
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MedKoo CAT#: 532463

CAS#: 1527473-30-8

Description: PF-06454589 is a potent and selective LRRK2 inhibitor.

Chemical Structure

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PF-06454589
CAS# 1527473-30-8
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 532463
Name: PF-06454589
CAS#: 1527473-30-8
Chemical Formula: C14H16N6O
Exact Mass: 284.14
Molecular Weight: 284.323
Elemental Analysis: C, 59.14; H, 5.67; N, 29.56; O, 5.63

Price and Availability

Size Price Availability Quantity
100mg USD 850
200mg USD 1450
500mg USD 2250
1g USD 3250
2g USD 5450
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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

Appearance: 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

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:

Product Data:
Product Data
Instruction:
View handling instruction
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/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 60.5 212.79

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.

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. 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.

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