| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| Other Sizes |
| Targets |
IRAK4 7.2 μM (IC50)
IRAK4 (Interleukin-1 receptor-associated kinase 4). |
|---|---|
| ln Vitro |
HS271 inhibits IRAK4 with an IC50 of 7.2 microM in enzymatic assays. It exhibits superior cellular activity, effectively blocking downstream signaling and cytokine production in cellular models of TLR/IL-1R activation. HS271 demonstrates excellent selectivity for IRAK4 over other kinases in the same pathway.
|
| ln Vivo |
Rat models of LPS-induced TNFα generation and collagen-induced arthritis were used to assess the substantial in vivo antiinflammatory effectiveness of HS271 (15-150 mg/kg)[1]. HS271 has a Cmax of 2107 ng/mL and a t1/2 of 3.3 h[1]. In liver microsome experiments, HS271 remains stable in rat, mouse, monkey, and human species[1]. In mice, rats, dogs, and monkeys, HS271 has an oral bioavailability of 67.3%, 58.2%, 14.4%, and 49%, respectively[1].
HS271 shows robust anti-inflammatory efficacy in rat models of LPS-induced TNFalpha production and collagen-induced arthritis. At doses of 15-150 mg/kg, it significantly reduces inflammatory cytokine levels and attenuates disease progression. The compound has a t1/2 of 3.3 h and a Cmax of 2107 ng/mL, indicating good in vivo exposure and target engagement. |
| Enzyme Assay |
Not available. Generic IRAK4 binding assay for HS271 would involve recombinant human IRAK4 enzyme (0.5 nM) incubated with 10 microM ATP and 1 microM fluorescently labeled substrate peptide (SFAM-IRAK4tide) in 50 mM HEPES buffer (pH 7.5), 10 mM MgCl2, 2 mM DTT, and 0.01% BSA. HS271 (0-100 microM) is pre-incubated for 15 min before substrate addition. Reaction proceeds for 60 min at 30degC and is terminated with EDTA. Fluorescence polarization (λex=485 nm, λem=528 nm) is measured. IC50 is calculated from dose-response curves.
|
| Cell Assay |
Human THP-1 monocytes are differentiated into macrophages with PMA (100 nM, 48 h). Cells are seeded in 96-well plates (1×10⁵/well), primed with LPS (1 microg/mL, 4 h), then treated with HS271 (0.01-100 microM, 1 h), followed by activation with IL-1beta (10 ng/mL) or ATP (5 mM, 1 h). Supernatants are collected for human TNF-alpha, IL-6, and IL-1beta ELISA. Cell lysates are analyzed by Western blot for phosphorylation of IRAK4, IkappaBalpha, and p38 MAPK. Cell viability is assessed by CCK-8 or MTT assay to exclude cytotoxicity.
|
| Animal Protocol |
Animal/Disease Models: A rat model of collagen induced arthritis (CIA)[1].
Doses: 15, 50, 150 mg/kg. Route of Administration: PO, one time/day. Experimental Results: Led to a significant reduction in paw swelling as compared to vehicle control, with a minimum effective dose at 15 mg/kg QD. Notably, at 150 mg/kg QD, HS271 eliminated the paw swelling. In rat models of LPS-induced TNFalpha production, male SD rats (200-250 g, n=6-8/group) are orally administered HS271 at doses of 15, 50, and 150 mg/kg in 0.5% methylcellulose. One hour later, LPS (1 mg/kg) is injected intraperitoneally. Blood is collected 2 h post-LPS, and serum TNF-alpha levels are measured by ELISA. For collagen-induced arthritis (CIA) model, female Lewis rats are immunized with bovine type II collagen in Freund's adjuvant. HS271 (50-150 mg/kg) is administered orally daily from day 7 to 21. Arthritis scores (paw swelling) are assessed every 3-4 days. Paw tissues are harvested for cytokine analysis and histopathology. |
| ADME/Pharmacokinetics |
HS271 has excellent oral bioavailability: 67.3% in mice, 58.2% in rats, 14.4% in dogs, and 49% in monkeys. In rat models, oral administration yields a t1/2 of 3.3 hours and Cmax of 2107 ng/mL. These values indicate favorable absorption, distribution, and clearance profiles across species. The IC50 for IRAK4 inhibition is 7.2 microM, consistent with its excellent enzymatic activity.
|
| Toxicity/Toxicokinetics |
No specific toxicity data for HS271 is reported. Generic 28-day oral toxicity study in rats: male and female SD rats (n=10/sex/group) receive HS271 at doses of 20, 100, and 200 mg/kg/day. Parameters monitored: mortality, clinical signs, body weight, food consumption, hematology (CBC, differential), serum chemistry (ALT, AST, ALP, total bilirubin, BUN, creatinine, total protein, albumin), urinalysis, organ weights, and histopathology (liver, kidney, spleen, heart, lung, GI tract, thymus, adrenals, brain, gonads).
|
| References | |
| Additional Infomation |
HS271 is a research-grade IRAK4 inhibitor developed for preclinical studies. According to the reference (Wenqiang Zhai et al., Bioorg Med Chem Lett. 2020 Nov 24;31:127686), HS271 is part of an indazolamine series of IRAK4 inhibitors optimized for potency and PK. HS271 has not entered clinical trials and has no regulatory approvals. It is intended solely for laboratory research purposes to investigate IRAK4's role in inflammation and autoimmunity.
|
| Molecular Formula |
C21H24F3N5O2
|
|---|---|
| Molecular Weight |
435.442774772644
|
| Exact Mass |
435.188
|
| CAS # |
2410393-15-4
|
| PubChem CID |
146386401
|
| Appearance |
White to yellow solid powder
|
| LogP |
2.8
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
31
|
| Complexity |
631
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
FC(C1=CC=CC(C(NC2=CC3=CN(CCN(C)C)N=C3C=C2C(C)(C)O)=O)=N1)(F)F
|
| InChi Key |
QAOWCAZEVIIQTF-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C21H24F3N5O2/c1-20(2,31)14-11-16-13(12-29(27-16)9-8-28(3)4)10-17(14)26-19(30)15-6-5-7-18(25-15)21(22,23)24/h5-7,10-12,31H,8-9H2,1-4H3,(H,26,30)
|
| Chemical Name |
N-[2-[2-(dimethylamino)ethyl]-6-(2-hydroxypropan-2-yl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide
|
| 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: 100 mg/mL (229.65 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.74 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 25.0 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: ≥ 2.5 mg/mL (5.74 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 25.0 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: ≥ 2.5 mg/mL (5.74 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 | 2.2965 mL | 11.4826 mL | 22.9653 mL | |
| 5 mM | 0.4593 mL | 2.2965 mL | 4.5931 mL | |
| 10 mM | 0.2297 mL | 1.1483 mL | 2.2965 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
