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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.
Physicochemical Properties
| Molecular Formula | C18H20FN3O4 |
| Molecular Weight | 361.3675 |
| Exact Mass | 361.143 |
| Elemental Analysis | C, 59.83; H, 5.58; F, 5.26; N, 11.63; O, 17.71 |
| CAS # | 1817626-54-2 |
| PubChem CID | 118414016 |
| Appearance | Off-white to yellow solid powder |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 621.0±55.0 °C at 760 mmHg |
| Flash Point | 329.4±31.5 °C |
| Vapour Pressure | 0.0±1.8 mmHg at 25°C |
| Index of Refraction | 1.607 |
| LogP | 0.19 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 26 |
| Complexity | 535 |
| Defined Atom Stereocenter Count | 3 |
| SMILES | F[C@]1([H])C(N([H])[C@]([H])(C([H])([H])OC2C3=C([H])C(=C(C(N([H])[H])=O)C([H])=C3C([H])=C([H])N=2)OC([H])([H])[H])[C@]1([H])C([H])([H])C([H])([H])[H])=O |
| InChi Key | JKDGKIBAOAFRPJ-ZBINZKHDSA-N |
| 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 |
| Chemical Name | 1-[[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxo-2-pyrrolidinyl]methoxy]-7-methoxy-6-isoquinolinecarboxamide |
| Synonyms | PF-06650833; Zimlovisertib; PF 06650833; PF06650833; PF-6650833; PF 6650833; PF6650833. |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| 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]. |
| 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]. |
| 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]. 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 Fragment-Based Drug Design. J Med Chem. 2017 Jul 13;60(13):5521-5542. [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. |
| Additional Infomation |
PF-06650833 is under investigation in clinical trial NCT02609139 (Study to Evaluate Pharmacokinetics of A Modified Release Formulation of PF-06650833 in Healthy Subjects). Zimlovisertib is an orally bioavailable, small molecule, reversible inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), with potential immunomodulating and anti-inflammatory activities. Upon oral administration, zimlovisertib targets, binds to, and blocks the kinase activity of IRAK4. This inhibits IRAK4-mediated signaling, prevents the activation of IRAK4-mediated nuclear factor-kappa B (NF-kB) signaling and decreases the expression of inflammatory cytokines. This may inhibit inflammation and immune-mediated cell destruction in inflammatory and auto-immune diseases where toll-like receptor (TLR) or interleukin 1 receptor (IL-1R) signaling is overactivated and MYD88 is dysregulated. IRAK4, a serine/threonine-protein kinase that plays a key role in both the TLR and IL-1R signaling pathways, is activated though the adaptor protein MYD88 and links the TLR and IL-1R signaling pathway to the NF-kB pathway. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~62.5 mg/mL (~172.95 mM) |
| 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. 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. 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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |