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| Targets |
PFE-360 targets leucine-rich repeat kinase 2 (LRRK2). LRRK2 is a kinase that has been implicated in the pathogenesis of Parkinson's disease. Mutations in LRRK2 are a common cause of familial Parkinson's disease. By inhibiting LRRK2 with high potency (IC50 = 2.3 nM), PFE-360 is being investigated as a disease-modifying therapy for Parkinson's disease.
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| ln Vitro |
In vitro, PFE-360 is a highly potent inhibitor of LRRK2, with an IC50 of 2.3 nM. It demonstrates excellent selectivity for LRRK2 over other kinases. Its ability to inhibit autophagy signaling has also been reported. These properties make it a valuable tool for studying LRRK2 biology and a promising drug candidate.
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| ln Vivo |
Treatment with PFE-360 (4 mg/kg and 7.5 mg/kg, interface, BID, 10–12 weeks) substantially decreased LRRK2-pSer935/total LRRK2 levels without causing any evident side effects [1].
In vivo, PFE-360 is orally active and brain-penetrant. It can reach the brain and inhibit LRRK2 activity. Its in vivo efficacy has been demonstrated in preclinical models of Parkinson's disease. Its ability to cross the blood-brain barrier is a critical feature for its application in treating neurological disorders. |
| Enzyme Assay |
In vitro kinase assays for PFE-360 measure its inhibition of LRRK2 activity. The compound is incubated with LRRK2 and a peptide substrate in the presence of ATP. The IC50 value of 2.3 nM is determined from dose-response curves. Selectivity against other kinases is assessed using broad kinase screening panels.
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| Cell Assay |
In vitro cell-based assays for PFE-360 involve treating cells with the compound and measuring LRRK2 phosphorylation levels. Its effects on autophagy signaling can also be assessed by measuring LC3-II levels or other autophagy markers. These assays confirm target engagement in a cellular context.
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| Animal Protocol |
Animal/Disease Models: Female Sprague Dawley rats (NTac:SD) weigh 225-250 grams [3].
Doses: 4 mg/kg and 7.5 mg/kg (pharmacokinetic/PK/PKs and pharmacodynamics). Route of Administration: Oral BID for 10-12 weeks. Experimental Results: The LRRK2-pSer935/total LRRK2 ratio diminished Dramatically both 1 hour and 12 hrs (hrs (hours)) after administration. Terminal body weight demonstrated no significant changes. In vivo animal experiments for PFE-360 have been conducted in models of Parkinson's disease. The compound is typically administered orally. Efficacy is assessed by measuring LRRK2 phosphorylation in brain tissue and by evaluating behavioral and neurochemical endpoints in disease models. |
| ADME/Pharmacokinetics |
PFE-360 has a molecular weight of 308.34 and a molecular formula of C16H16N6O. It is a solid with a purity of ≥98%. It is soluble in DMSO (≥17.37 mg/mL) but insoluble in ethanol and water. It is typically stored at -20°C.
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| Toxicity/Toxicokinetics |
PFE-360 is for research use only and is not intended for human use. Its safety profile is being evaluated in preclinical studies. As a potent LRRK2 inhibitor, its toxicity is related to its mechanism of action. Standard safety precautions should be taken when handling.
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| References |
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| Additional Infomation |
PFE-360 (PF-06685360) is a potent, selective, brain-penetrant, and orally active LRRK2 inhibitor. It has an IC50 of 2.3 nM. It is being developed for the potential treatment of Parkinson's disease. PFE-360 inhibits LRRK2 kinase activity and autophagy signaling. It is a research compound with applications in neuroscience and drug discovery.
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| Molecular Formula |
C16H16N6O
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| Molecular Weight |
308.33784198761
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| Exact Mass |
308.138
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| CAS # |
1527475-61-1
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| PubChem CID |
89915073
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| Appearance |
Off-white to gray solid powder
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| LogP |
1.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
23
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| Complexity |
472
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1CCN(C2=C3C(=NC=N2)NC=C3C2C=C(C#N)N(C)C=2)CC1
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| InChi Key |
IYQTYHISVSPMSU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H16N6O/c1-21-9-11(6-12(21)7-17)13-8-18-15-14(13)16(20-10-19-15)22-2-4-23-5-3-22/h6,8-10H,2-5H2,1H3,(H,18,19,20)
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| Chemical Name |
1-methyl-4-(4-morpholin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrrole-2-carbonitrile
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| Synonyms |
PFE360; PFE 360; PFE-360
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~10.42 mg/mL (~33.79 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.04 mg/mL (3.37 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.4 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.04 mg/mL (3.37 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.4 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1.04 mg/mL (3.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2432 mL | 16.2159 mL | 32.4317 mL | |
| 5 mM | 0.6486 mL | 3.2432 mL | 6.4863 mL | |
| 10 mM | 0.3243 mL | 1.6216 mL | 3.2432 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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