| Size | Price | Stock | Qty |
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| 25mg |
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Purity: ≥98%
PF06650833 is a novel, potent and selective inhibitor of Interleukin-1 receptor associated kinase 4 (IRAK4) which is used to treat autoimmune diseases such as rheumatoid arthritis, lupus, and lymphomas. RAK4 is located proximal to TLR/IL-1 receptors, and in preclinical studies, inhibits downstream signaling from these receptors. The development of novel small molecule inhibitors of this kinase has the potential to lead to new therapeutics to treat diseases such as rheumatoid arthritis, lupus, and lymphomas.
| ln Vitro |
At an inhibitor dose of 200 nM, the ATP Km of each of the 278 kinases in the panel (Invitrogen) was used to assess the kinome selectivity profile of zimlovisertib (compound 40). It was found that IRAK4's inhibition rate was almost 100% [1]. Using a whole-cell functional VEGF2R test (PAE-KDR cell line), lactam zimlovisertib was assessed. At doses up to and including 30 μM, no action was seen. Zimlovisertib reduced hERG currents by 25% at 100 μM in voltage clamp tests [1]. CYP450 enzyme probe substrates and pooled human liver microsomes were used to assess Zimlovisertib's capacity to inhibit the five primary CYP450 enzymes. Less than 5% inhibition of CYPs 1A2, 2C8, 2C9, 2D6, and 3A4 was seen at a 3 μM Zimlovisertib dose. Using pooled human liver microsomes and probe substrates, the time-dependent inhibition of six key CYP450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6) by lactam zimlovisertib was investigated. There was no evidence of time-dependent CYP inhibition at 100 μM zimlovisertib. Cryopreserved human hepatocytes were used to assess Zimlovisertib's potential induction of CYP3A, and the results showed a 4.4-fold rise in mRNA at 10 μM [1].
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| ln Vivo |
In a dose-dependent manner, zimlovisertib (0.3-30 mg/kg; p.o.; 2.5 hours) dramatically reduced LPS-induced TNF-α in male Sprague-Dawley rats. 2.5 hours after oral dosing, the mean plasma zimlovisertib exposures were 2.1 nM, 7.7 nM, 19 nM, and 150 nM at 0.3, 1, 3, and 30 mg/kg, in that order. Rat plasma contains 0.3 percent unbound zimlovisertib [1].
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| Animal Protocol |
Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat[1]
Doses: 0.1 mg/kg, 1 mg/kg, 3 mg/kg, 30 mg/kg Route of Administration: po (po (oral gavage)) 20 mg/kg. 2.5 hour Experimental Results: Significant inhibition of LPS-induced TNF-α in a dose-dependent manner. |
| References |
[1]. Lee KL, et al. Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragmen
[2]. Seganish WM. Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015). Expert Opin Ther Pat. 2016 Aug;26(8):917-32. |
| Molecular Formula |
C18H20FN3O4
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|---|---|
| Molecular Weight |
361.3675
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| CAS # |
1817626-54-2
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| SMILES |
O=C(C1=CC2=C(C(OC[C@H]([C@H](CC)[C@@H]3F)NC3=O)=NC=C2)C=C1OC)N
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| InChi Key |
JKDGKIBAOAFRPJ-ZBINZKHDSA-N
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| InChi Code |
InChI=1S/C18H20FN3O4/c1-3-10-13(22-17(24)15(10)19)8-26-18-11-7-14(25-2)12(16(20)23)6-9(11)4-5-21-18/h4-7,10,13,15H,3,8H2,1-2H3,(H2,20,23)(H,22,24)/t10-,13+,15-/m0/s1
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| Chemical Name |
1-[[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxo-2-pyrrolidinyl]methoxy]-7-methoxy-6-isoquinolinecarboxamide
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| Synonyms |
PF-06650833; Zimlovisertib; PF 06650833; PF06650833; PF-6650833; PF 6650833; PF6650833.
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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 : ~62.5 mg/mL (~172.95 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.76 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 20.8 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: ≥ 2.08 mg/mL (5.76 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 20.8 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: ≥ 2.08 mg/mL (5.76 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 | 2.7672 mL | 13.8362 mL | 27.6725 mL | |
| 5 mM | 0.5534 mL | 2.7672 mL | 5.5345 mL | |
| 10 mM | 0.2767 mL | 1.3836 mL | 2.7672 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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