| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| Other Sizes |
| Targets |
IRAK4-IN-1 (compound 23) was shown to have an EC50 of 2300 nM in rat whole blood (RWB) when its in vitro metabolic stability profile was evaluated [1].
|
|---|---|
| ln Vitro |
IRAK4-IN-1 (compound 23) was shown to have an EC50 of 2300 nM in rat whole blood (RWB) when its in vitro metabolic stability profile was evaluated [1].
Compound 23 (representative of the optimized series, referred to by user as IRAK4-IN-1) inhibited IRAK4 with an IC₅₀ of 7 nM in an enzymatic assay. [1] In a human peripheral blood mononuclear cell (hPBMC) assay stimulated with the TLR7 agonist Resiquimod (R848), compound 23 exhibited an EC₅₀ of 300 nM. In rat whole blood (RWB) stimulated with R848, its EC₅₀ was 2300 nM. [1] Compound 23 demonstrated excellent kinase selectivity. When tested against a panel of 265 kinases, 98.9% of the kinases had IC₅₀ values more than 100-fold weaker than its IRAK4 IC₅₀. [1] The permeability of compound 23 was measured in MDCKII cells, showing a Papp value of 41 × 10⁻⁶ cm/s. [1] The in vitro metabolic stability of compound 23 was assessed in rat hepatocytes, showing a clearance (Clint) of 36 L/h/kg. [1] |
| ln Vivo |
IRAK4-IN-1 (compound 23) has a low plasma clearance (Clp=22 mL/min/kg) and a high bioavailability of 73%, which contribute to its tolerable half-life of 1.3 h, according to oral pharmacokinetic studies [1].
In a rat TLR7-driven inflammation model, oral administration of compound 23 (dosed at 5.7 and 12 mg/kg, 1 hour pre-treatment) significantly and dose-dependently inhibited the secretion of serum IL-6 induced by intraperitoneal injection of the TLR7 agonist R848 (5 mg/kg). [1] |
| Enzyme Assay |
An enzymatic assay was used to measure IRAK4 inhibition. The specific detailed protocol for the IRAK4 kinase inhibition assay is described in the supplementary materials of the article, which includes experimental conditions for determining compound IC₅₀ values. [1]
|
| Cell Assay |
Human Peripheral Blood Mononuclear Cell (hPBMC) Assay: hPBMCs were stimulated with the TLR7 agonist Resiquimod (R848) to assess the cellular potency of compounds in inhibiting IRAK4-dependent signaling. The production of cytokines or other relevant readouts was measured to determine compound EC₅₀ values. [1]
Rat Whole Blood (RWB) Assay: Rat whole blood was stimulated with R848 to evaluate compound potency in a more physiologically relevant matrix containing plasma proteins. Cytokine release (e.g., IL-6) was measured to determine the whole blood EC₅₀. [1] Permeability Assay (MDCKII): The apparent permeability (Papp) of compounds was measured using MDCKII cell monolayers to assess passive cellular permeability. [1] Hepatocyte Metabolic Stability Assay: The in vitro intrinsic clearance (Clint) of compounds was determined using rat hepatocytes to predict hepatic metabolic stability. [1] |
| Animal Protocol |
Rat TLR7-Driven Inflammation Model: Female Lewis rats were used. Compound 23 was administered orally (vehicle not specified in main text, details in supplementary material) at specified doses (5.7 and 12 mg/kg) 1 hour prior to intraperitoneal (i.p.) challenge with the TLR7 agonist Resiquimod (R848) at 5 mg/kg. Blood samples were collected 1.5 hours after R848 challenge. Serum levels of the cytokine IL-6 were measured to assess the anti-inflammatory effect of the compound. [1]
|
| ADME/Pharmacokinetics |
In rats, compound 23 exhibited high oral bioavailability (73%), low plasma clearance (Clp = 22 mL/min/kg), and a half-life (t₁/₂) of 1.3 hours. [1]
|
| References | |
| Additional Infomation |
IRAK4-IN-1 (compound 23) is a 4,6-disubstituted quinazoline inhibitor discovered through optimization of lead compounds via high-throughput screening. [1]
The design of this compound was guided by structure-based drug design, utilizing the X-ray co-crystal structure of an earlier lead compound bound to IRAK4. The key interaction involves a salt bridge between the quinazoline C4-amino group and ASP 272 at the IRAK4 active site. [1] The medicinal chemistry research focused on optimizing the C4-amino and C6-substituents on the quinazoline core to balance the inhibitory activity, kinase selectivity, and physicochemical properties of IRAK4 (e.g., reducing pKa and modulating lipophilicity). [1] This series of IRAK4 inhibitors is intended for the treatment of inflammatory diseases such as rheumatoid arthritis, irritable bowel syndrome, asthma, and systemic lupus erythematosus. [1] |
| Molecular Formula |
C19H23N5O
|
|---|---|
| Molecular Weight |
337.418823480606
|
| Exact Mass |
337.19
|
| CAS # |
1820787-94-7
|
| PubChem CID |
118475349
|
| Appearance |
White to off-white solid powder
|
| LogP |
2.6
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
25
|
| Complexity |
478
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
O1CCN(CC1)C1CCC(CC1)NC1C2C=C(C#N)C=CC=2N=CN=1
|
| InChi Key |
HVQXFGHHSFTACS-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C19H23N5O/c20-12-14-1-6-18-17(11-14)19(22-13-21-18)23-15-2-4-16(5-3-15)24-7-9-25-10-8-24/h1,6,11,13,15-16H,2-5,7-10H2,(H,21,22,23)
|
| Chemical Name |
4-[(4-morpholin-4-ylcyclohexyl)amino]quinazoline-6-carbonitrile
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~14.29 mg/mL (~42.35 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.43 mg/mL (4.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 14.3 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9637 mL | 14.8183 mL | 29.6367 mL | |
| 5 mM | 0.5927 mL | 2.9637 mL | 5.9273 mL | |
| 10 mM | 0.2964 mL | 1.4818 mL | 2.9637 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
