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Purity: ≥98%
WAY-262611 (WAY262611) is a novel agonist of the wingless β-Catenin pathway with the potential for the treatment of bone disorders. It increases bone formation rate with EC50 of 0.63 uM in TCF-Luciferase assay. WAY-262611 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration. WAY-262611 acts via the Wnt β-catenin pathway and most likely through inhibition of Dkk-1. WAY-262611 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration. WAY-262611 was discovered from a high-throughput screening (HTS) campaign to discover small molecule leads for the treatment of bone disorders concluded with the discovery of a compound with a 2-aminopyrimidine template that targeted the Wnt beta-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and molecular properties led to the discovery of (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine (5, WAY-262611).
| Targets |
WAY-262611 targets the wingless/β-catenin signaling pathway as an agonist [1]
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| ln Vitro |
With its modest kinase inhibition potential, high solubility, and most powerful activity in the primary assay, WAY-262611 stands out[1].
WAY-262611 activated the canonical Wnt/β-catenin signaling pathway in osteoblastic cells, as demonstrated by increased nuclear accumulation of β-catenin and upregulation of Wnt target genes (e.g., Axin2, Runx2) at the mRNA and protein levels [1] - WAY-262611 enhanced osteoblast differentiation and mineralization in primary murine calvarial osteoblasts and MC3T3-E1 cells, evidenced by increased alkaline phosphatase (ALP) activity (a marker of early osteoblast differentiation) and matrix mineralization (assessed by alizarin red staining) [1] |
| ln Vivo |
After oral administration, WAY-262611 exhibits dose-dependent increase in the trabecular bone formation rate in ovariectomized rats and excellent pharmacokinetic properties. Calvariae from WAY-262611-treated wt mice exhibit statistically higher BFR, whereas similarly treated KO animals do not differ from the control group. This suggests that WAY-262611 is likely inhibiting Dkk-1 and acting through the Wnt β-catenin pathway[1].
Daily oral administration of WAY-262611 (dose not specified) to adult mice for 28 days significantly increased the bone formation rate (assessed by calcein double labeling) in the trabecular bone of the distal femur; it also increased trabecular bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N), while decreasing trabecular separation (Tb.Sp) [1] - WAY-262611 treatment did not affect bone resorption markers (e.g., serum CTX-1 levels) or body weight in mice, indicating a specific effect on bone formation without overt systemic side effects [1] |
| Enzyme Assay |
WAY-262611 is a novel agonist of the wingless β-Catenin pathway that increases bone formation rate with EC50 of 0.63 uM in TCF-Luciferase assay. WAY-262611 has the most potent activity in the primary assay, low kinase inhibition potential, and high solubility.
Wnt/β-catenin signaling activation assay: Osteoblastic cells (MC3T3-E1 or primary murine calvarial osteoblasts) were treated with serial concentrations of WAY-262611 (or vehicle control) for 24–72 h; nuclear and cytoplasmic fractions were isolated to detect β-catenin localization via Western blotting; quantitative real-time PCR (qRT-PCR) was performed to measure the mRNA expression of Wnt target genes (Axin2, Runx2), and Western blotting was used to verify protein levels of these genes [1] |
| Cell Assay |
Osteoblast differentiation assay: Primary murine calvarial osteoblasts and MC3T3-E1 cells were seeded in culture plates and treated with WAY-262611 (or DMSO as vehicle) at different concentrations; alkaline phosphatase (ALP) activity was measured at day 7 (early differentiation stage) using a colorimetric assay; matrix mineralization was evaluated at day 21 by alizarin red staining, and the stained mineralized nodules were quantified via spectrophotometry after solubilization [1]
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| Animal Protocol |
Rats: WAY-262611 is dissolved in DMSO and diluted with saline for iv (Rats). WAY-262611 is prepared in 0.5% methylcellulose/2% Tween-80 for po OVX rats14 are treated orally with 5 (po, vehicle=0.5% methylcellulose/2% Tween-80, qd, 28 days) at four doses. Trabecular bone formation rate (BFR) in the tibia is established in all dose groups at the end of the in-life portion of the study. A clear dose response and activity as low as 0.3 mg/kg/day are observed;
Mice: To confirm activity via the Wnt pathway, the calvariae of wild type (wt) and Dkk-1 knockout (KO) mice are treated with 5 once a day for 7 days (DMSO solution, sc injection). The KO animals are not expected to respond because of the inherent inability to inhibit a missing target protein, while wild type animals with fully expressed Dkk-1 are expected to show a pharmacological response. Ovariectomized rats and mice Bone formation assessment in adult mice: Adult mice were randomly divided into treatment and control groups; the treatment group received daily oral gavage of WAY-262611 for 28 consecutive days, while the control group received vehicle alone; calcein double labeling was performed (calcein injected intraperitoneally at day 7 and day 1 before sacrifice) to assess bone formation rate; at the end of the treatment period, mice were euthanized, distal femurs were harvested, and bone histomorphometric analysis (BV/TV, Tb.Th, Tb.N, Tb.Sp) was conducted on undecalcified bone sections; serum samples were collected to measure CTX-1 levels (a bone resorption marker) via ELISA, and body weight was monitored weekly [1] |
| Toxicity/Toxicokinetics |
During a 28-day oral administration period in mice, WAY-262611 did not show significant systemic toxicity, and there was no significant change in body weight compared to the control group [1].
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| References |
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| Additional Infomation |
[1-[4-(2-naphthyl)-2-pyrimidinyl]-4-piperidinyl]methylamine is a naphthalene compound. WAY-262611 (chemical name: (1-(4-(naphthyl-2-yl)pyrimidin-2-yl)piperidin-4-yl)methylamine) is a small molecule Wnt/β-catenin signaling pathway agonist specifically designed to enhance bone formation [1] - The classic Wnt/β-catenin signaling pathway plays a central role in regulating osteoblast differentiation and bone formation; activating this pathway promotes osteoblast maturation and mineralization, thereby increasing the quality of trabecular bone in vivo [1] - WAY-262611 is a potential treatment for osteoporosis and other bone loss disorders because it selectively increases bone formation without affecting bone resorption [1]
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| Molecular Formula |
C20H22N4
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| Molecular Weight |
318.42
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| Exact Mass |
318.184
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| CAS # |
1123231-07-1
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| Related CAS # |
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| PubChem CID |
25199517
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
544.8±42.0 °C at 760 mmHg
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| Flash Point |
283.3±27.9 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.638
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| LogP |
4.09
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
24
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| Complexity |
393
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
QHLITPHIARVDJI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H22N4/c21-14-15-8-11-24(12-9-15)20-22-10-7-19(23-20)18-6-5-16-3-1-2-4-17(16)13-18/h1-7,10,13,15H,8-9,11-12,14,21H2
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| Chemical Name |
[1-(4-naphthalen-2-ylpyrimidin-2-yl)piperidin-4-yl]methanamine
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| Synonyms |
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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) |
DMSO: ~64 mg/mL ( 200.99 mM)
Water: <10 mg/mL Ethanol: <10 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (5.24 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 16.7 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: ≥ 1.67 mg/mL (5.24 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 16.7 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: ≥ 1.67 mg/mL (5.24 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 | 3.1405 mL | 15.7025 mL | 31.4051 mL | |
| 5 mM | 0.6281 mL | 3.1405 mL | 6.2810 mL | |
| 10 mM | 0.3141 mL | 1.5703 mL | 3.1405 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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