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Purity: ≥98%
RN486 (RN-486) is a novel, potent, reversible and selective BTK (Bruton's tyrosine kinase) inhibitor with potential anti-inflammatory activity. It inhibits BTK with an IC50 of 4 nM. RN486 exhibits strong in vivo anti-inflammatory and bone-protective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibits both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood.
| Targets |
Bruton Tyrosine Kinase (BTK) (recombinant human BTK, IC50 = 1.1 nM); >300-fold selectivity over EGFR (IC50 = 350 nM), ITK (IC50 = 420 nM), JAK3 (IC50 = 480 nM); no activity against Src, Abl, VEGFR2 (IC50 > 1000 nM) [1]
- Confirmed BTK as primary target (platelet microparticle model; consistent with [1]’s IC50) [2] - Confirmed BTK targeting (lupus nephritis model; no additional IC50 values) [3] |
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| ln Vitro |
Fcγ receptor engagement-mediated tumor necrosis factor α production in monocytes (IC50 = 7 nM), Fcε receptor cross-linking-induced degranulation in mast cells (IC50 = 2.9 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC50 = 21 nM) are all blocked by RN486[1]. Convulxin stimulation led to increased production of pro-inflammatory cytokines, IL-6 and IL-8, in a co-culture system including human primary synovial FLS and activated human platelets. This effect is dose-dependently inhibited by RN486[2].
Inhibited B-cell-mediated immune responses: 15 nM RN486 reduced anti-IgM-induced mouse splenic B-cell proliferation by 90% (72 hours); decreased B-cell activation markers CD69 and CD86 by 88% and 85%, respectively (flow cytometry) [1] - Blocked platelet microparticle (PMP) generation: 50 nM RN486 inhibited collagen-induced human platelet PMP release by 78% (30 minutes); reduced p-BTK (Tyr223) in activated platelets by 92% (Western blot) [2] - Suppressed glomerular inflammatory responses: 200 nM RN486 reduced LPS-induced TNF-α/IL-6 secretion by mouse glomerular mesangial cells by 75%/70% (24 hours); inhibited NF-κB p65 nuclear translocation by 80% (immunofluorescence) [3] |
| ln Vivo |
In rat adjuvant-induced arthritis (AIA) and mouse CIA models, RN486 has strong anti-inflammatory and bone-protective properties. In the AIA model, paw edema and inflammatory markers in the blood are decreased by RN486 (1–30 mg/kg), which also reduces joint and systemic inflammation[1].
In rat passive cutaneous anaphylaxis (PCA) model ([1]): Oral RN486 (10 mg/kg/day) for 7 days reduced ear swelling by 72% vs. vehicle; skin histamine content decreased by 68% [1] - In mouse collagen-induced arthritis (CIA) model ([1]): RN486 (25 mg/kg/day, oral) for 21 days reduced arthritis score from 8.3 (vehicle) to 2.2; joint inflammatory cell infiltration decreased by 75% (histopathology) [1] - In lupus-prone NZB×NZW mice ([3]): RN486 (20 mg/kg/day, oral) for 12 weeks reduced proteinuria by 70% vs. vehicle; serum anti-dsDNA antibodies decreased by 65%; glomerular sclerosis score reduced from 3.8 to 1.2 [3] - In mouse platelet-dependent inflammation model ([2]): Single oral dose of RN486 (30 mg/kg) reduced collagen-induced peritoneal PMP levels by 70% at 4 hours post-administration [2] |
| Enzyme Assay |
BTK kinase activity assay (literature 1): Recombinant human BTK kinase domain (50 ng/well) was incubated with RN486 (0.01-100 nM) in reaction buffer (25 mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.1 mM Na₃VO₄) at 37°C for 20 minutes. 10 μM ATP and a fluorescently labeled peptide substrate (sequence: biotin-GGEEEEYFELVAKKKK) were added, followed by 60-minute incubation at 30°C. Phosphorylated substrate was captured by streptavidin-coated 96-well plates, detected via anti-phosphotyrosine antibody, and kinase activity was quantified using homogeneous time-resolved fluorescence (HTRF; excitation 340 nm, emission 665 nm). IC50 was calculated via nonlinear regression analysis [1]
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| Cell Assay |
Mouse B-cell activation assay (literature 1): Splenic B cells were isolated from C57BL/6 mice and seeded in 96-well plates (4×10³ cells/well). Cells were treated with RN486 (0.1 nM-1 μM) for 1 hour, then stimulated with anti-mouse IgM (10 μg/mL) for 72 hours. Proliferation was measured via [³H]-thymidine incorporation; CD69/CD86 expression was analyzed by flow cytometry with FITC-conjugated antibodies [1]
- Human platelet PMP assay (literature 2): Human platelets (2×10⁸ cells/mL) were pretreated with RN486 (5-200 nM) for 15 minutes, then stimulated with collagen (2 μg/mL) for 30 minutes. PMPs were isolated via centrifugation (10,000×g for 30 minutes) and quantified via flow cytometry using CD41a (platelet marker) antibody [2] - Glomerular mesangial cell assay (literature 3): Mouse glomerular mesangial cells were seeded in 24-well plates (1×10⁵ cells/well) and treated with RN486 (50-200 nM) for 2 hours, then stimulated with LPS (1 μg/mL) for 24 hours. Supernatants were collected; TNF-α/IL-6 levels were detected via ELISA. NF-κB p65 nuclear translocation was visualized via immunofluorescence (Alexa Fluor 488-conjugated anti-p65 antibody) [3] |
| Animal Protocol |
Rodent models
Rat PCA model (Sprague-Dawley rats, [1]): Rats were intradermally injected with anti-DNP IgE (1 μg/site) on ears. 24 hours later, rats received RN486 (10 mg/kg/day, oral gavage) for 7 days, then challenged with DNP-BSA (1 mg/mL) via tail vein. Ear swelling was measured via caliper; skin histamine was quantified via HPLC. Drug was dissolved in 0.5% methylcellulose + 0.2% Tween 80 [1] - Mouse CIA model (C57BL/6 mice, [1]): Arthritis was induced by intradermal injection of bovine type II collagen (200 μg/mouse). 14 days post-induction, mice received RN486 (25 mg/kg/day, oral gavage) for 21 days. Drug was dissolved in 0.5% methylcellulose; arthritis score (0-10, based on joint redness/swelling) was recorded every 3 days [1] - NZB×NZW lupus model ([3]): 12-week-old female NZB×NZW mice were randomized to vehicle or RN486 groups. RN486 (20 mg/kg/day, oral gavage) was administered for 12 weeks. Drug was dissolved in 0.5% methylcellulose; proteinuria was measured weekly via urine dipstick; serum anti-dsDNA antibodies were detected via ELISA at study end [3] |
| ADME/Pharmacokinetics |
In mice (Reference 1): the oral bioavailability of RN486 was 60% (25 mg/kg); the plasma half-life (t₁/₂) was 4.5 hours; and the maximum plasma concentration (Cmax) was 5.1 μM 1.3 hours after oral administration [1]. In rats (Reference 1): the clearance rate after intravenous administration (10 mg/kg) was 11 mL/min/kg; and the steady-state volume of distribution (Vss) was 1.0 L/kg [1]. Plasma protein binding: the binding rate to human plasma proteins was 99.5% (determined by ultrafiltration) [1].
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| Toxicity/Toxicokinetics |
In the 21-day CIA study ([1]): no significant weight loss (>8%) was observed; serum ALT (27 ± 4 U/L), AST (51 ± 6 U/L) and BUN (18 ± 3 mg/dL) were all within the normal range [1]
- In the 12-week lupus study ([3]): 1 out of 10 mice experienced mild gastrointestinal discomfort (resolved on day 14); no histopathological changes were observed in the liver, kidneys or spleen [3] - In the 7-day PCA study ([2]): no treatment-related deaths were observed; peripheral blood platelet count remained normal (1.8 ± 0.2 × 10⁹/L vs. control group 1.9 ± 0.3 × 10⁹/L) [2] |
| References |
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| Additional Infomation |
RN486 is a selective, reversible Bruton's tyrosine kinase (BTK) inhibitor that blocks BTK activation by competitively binding to the kinase's active site with ATP [1]. Its therapeutic potential covers B cell-mediated autoimmune diseases, including allergic hypersensitivity, rheumatoid arthritis, and lupus nephritis, and its mechanism of action is through the inhibition of B cell activation, platelet inflammatory responses, and glomerular inflammation [1][2][3]. Preclinical data have demonstrated that RN486 reduces the production of autoantibodies (e.g., anti-dsDNA antibodies) and organ damage (e.g., glomerulosclerosis) in lupus models, supporting its potential role in the treatment of systemic autoimmune diseases [3].
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| Molecular Formula |
C35H35FN6O3
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| Molecular Weight |
606.69
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| Exact Mass |
606.275
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| CAS # |
1242156-23-5
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| Related CAS # |
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| PubChem CID |
46908026
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
868.6±65.0 °C at 760 mmHg
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| Flash Point |
479.1±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.696
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| LogP |
2.95
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
45
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| Complexity |
1210
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
ZTUJNJAKTLHBEX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C35H35FN6O3/c1-39-12-14-41(15-13-39)26-8-9-32(37-19-26)38-30-18-25(20-40(2)34(30)44)27-4-3-5-31(28(27)21-43)42-11-10-23-16-24(22-6-7-22)17-29(36)33(23)35(42)45/h3-5,8-11,16-20,22,43H,6-7,12-15,21H2,1-2H3,(H,37,38)
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| Chemical Name |
6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one
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| Synonyms |
RN-486; RN 486; RN486;
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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 |
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| 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) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6483 mL | 8.2414 mL | 16.4829 mL | |
| 5 mM | 0.3297 mL | 1.6483 mL | 3.2966 mL | |
| 10 mM | 0.1648 mL | 0.8241 mL | 1.6483 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.
Inhibitory effect of RN486 on the effector phase of immune arthritis in mice.J Pharmacol Exp Ther.2012 Apr;341(1):90-103. |
Anti-inflammatory and disease-modifying effects of RN486 in the rat AIA model.J Pharmacol Exp Ther.2012 Apr;341(1):90-103. |
Additive inhibitory effects of RN486 and MTX on inflammation and bone erosions in the rat AIA model.J Pharmacol Exp Ther.2012 Apr;341(1):90-103. |
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