| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
Target: RARγ (binding Ki = 1.1 ± 0.3 nM; functional Kb = 7.1 ± 4.9 nM, max inhibition >100% in cell-based co-transfection assay)
RARα (binding Ki >1700 nM; functional Kb >4440 nM) RARβ (binding Ki >2980 nM; functional Kb = 1510 nM) [1] |
|---|---|
| ln Vitro |
In tests, it was found that LY2955303 bound RARα, RARβ, and RARγ with Ki values of >1700, >2980, and 1.09 nM, respectively. RARγ has a functioning Ki of 7.1±4.9 nM[1].
In Vitro: LY2955303 demonstrated high binding affinity and selectivity for RARγ over RARα and RARβ. Binding Ki values: RARγ = 1.1 ± 0.3 nM, RARα >1700 nM (selectivity >1560-fold), RARβ >2980 nM (selectivity >2744-fold). [1] In a cellular co-transfection functional assay using HEK293 cells, LY2955303 acted as a potent RARγ antagonist with Kb = 7.1 ± 4.9 nM and maximum inhibition >100%. For RARα, Kb >4440 nM; for RARβ, Kb = 1510 nM. [1] As a zwitterion, LY2955303 showed dramatically improved solubility >1.0 mg/mL in simulated intestinal fluid. [1] |
| ln Vivo |
A dose-response impact was demonstrated by the single-shot barrier LY2955303, and the weight-bearing variance (ED50=0.72 mg/kg) was decreased by the trap [1].
In Vivo: In the rat mono-iodoacetate (MIA) model of osteoarthritis-like joint pain, a single oral dose of LY2955303 produced a dose-responsive reduction in differential weight bearing (a measure of joint pain), with an ED50 of 0.72 mg/kg. The maximal analgesic response was similar to that of other analgesics. [1] In a 14-day toxicology study in rats, LY2955303 showed no adverse testicular effects at 10 mg/kg (margin of exposure 59-fold over the efficacious exposure at ED50), while testicular degeneration was observed at 30 mg/kg (margin of exposure 239-fold). [1] |
| Cell Assay |
Cell Assay: Functional antagonist activity was determined using human embryonic kidney HEK293 cells transiently transfected with a hybrid GAL4 DNA binding domain (DBD) fused to the RARγ, RARα, or RARβ ligand binding domain (LBD) downstream of an SV40 promoter, and a reporter plasmid containing 5× GAL4 response element upstream of a firefly luciferase gene. Antagonist activity was measured in the presence of all-trans retinoic acid (ATRA) at the corresponding EC80 concentrations (15 nM for RARα and RARγ, 10 nM for RARβ). Percent inhibition was calculated based on the response obtained in the presence (baseline) and absence (100% inhibition) of ATRA alone. IC50 was calculated using a 4-parameter logistic fit, and an apparent Kb was calculated using the Cheng-Prusoff equation with the EC50 of ATRA determined within each assay. All reported data derived from at least 3 replicates. [1]
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| Animal Protocol |
Animal Protocol: Rat mono-iodoacetate (MIA) model of osteoarthritis-like joint pain: A single intra-articular injection of MIA into a hind limb joint was performed. At nine days post-injection, differential weight bearing between contralateral and ipsilateral limbs was approximately 22 g. On the same day, a single oral dose of LY2955303 was administered to evaluate dose-responsive analgesic effect (ED50 = 0.72 mg/kg). [1]
Rat pharmacokinetic study: Oral administration of LY2955303 at doses of 10, 30, and 100 mg/kg showed proportional increases in Cmax and AUC, with no accumulation upon chronic dosing up to 14 days. [1] Rat 14-day toxicology study: LY2955303 was administered orally to assess testicular adverse effects. Doses evaluated included 0.72 mg/kg (ED50), 10 mg/kg (no adverse effect level), and 30 mg/kg (testicular degeneration observed). [1] |
| ADME/Pharmacokinetics |
ADME/Pharmacokinetics: Oral bioavailability of LY2955303 in rats was 26% (determined from 2 mg/kg IV and 10 mg/kg PO). [1]
In rats, oral administration at 10, 30, and 100 mg/kg resulted in proportional increases in Cmax and AUC, with no accumulation upon chronic dosing up to 14 days. [1] Solubility in simulated intestinal fluid was >1.0 mg/mL due to the compound being a zwitterion. [1] |
| Toxicity/Toxicokinetics |
Toxicity/Toxicokinetics: In a 14-day toxicology study in rats, LY2955303 showed no adverse testicular effects at an oral dose of 10 mg/kg (margin of exposure 59-fold over exposure at the efficacious ED50 of 0.72 mg/kg, where exposure AUC was 154 ng·h/mL at ED50 and 9100 ng·h/mL at 10 mg/kg). Testicular degeneration was observed at 30 mg/kg (exposure AUC = 36,800 ng·h/mL; margin of exposure 239-fold). [1]
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| References | |
| Additional Infomation |
Additional Info: Retinoic acid receptors (RARα, β, γ) are nuclear receptors that act as ligand-activated transcription factors. All-trans retinoic acid (ATRA), the natural RAR ligand, is deleterious to articular cartilage and associated with cartilage breakdown in osteoarthritis. RAR antagonists may prevent or reverse retinoid-mediated cartilage destruction and mitigate OA pain. [1]
Previous pan-RAR antagonist BMS-189453 showed efficacy in rodent joint pain models but caused unacceptable testicular adverse effects at doses as low as 2 mg/kg in rats. Genetic studies indicated testicular degeneration in RARα knockout mice but not RARγ knockout mice, supporting the hypothesis that selective RARγ antagonism could avoid testicular toxicity. LY2955303 was designed to achieve >1000-fold selectivity for RARγ over RARα and RARβ, and it demonstrated efficacy in the MIA model at exposures significantly lower than those causing testicular toxicity, consistent with an improved safety profile. [1] |
| Molecular Formula |
C36H42N4O3
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|---|---|
| Molecular Weight |
578.743689060211
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| Exact Mass |
578.325
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| CAS # |
1433497-19-8
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| PubChem CID |
71552369
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| Appearance |
White to off-white solid powder
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| LogP |
5.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
43
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| Complexity |
927
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C=CC(=CC=1)N1C(=CC(C2C=CC(C(=O)O)=CC=2)=N1)C1C=C(C=C(C=1)C(C)(C)C)C(C)(C)C)N1CCN(C)CC1
|
| InChi Key |
YVXYHNKIOFSFMZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C36H42N4O3/c1-35(2,3)28-20-27(21-29(22-28)36(4,5)6)32-23-31(24-8-10-26(11-9-24)34(42)43)37-40(32)30-14-12-25(13-15-30)33(41)39-18-16-38(7)17-19-39/h8-15,20-23H,16-19H2,1-7H3,(H,42,43)
|
| Chemical Name |
4-(5-(3,5-di-tert-butylphenyl)-1-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-pyrazol-3-yl)benzoic acid
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| Synonyms |
LY-2955303; LY2955303; LY 2955303.
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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 |
| 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 : ~30 mg/mL (~51.84 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (3.46 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 20.0 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. Solubility in Formulation 2: ≥ 2 mg/mL (3.46 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 20.0 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 | 1.7279 mL | 8.6395 mL | 17.2789 mL | |
| 5 mM | 0.3456 mL | 1.7279 mL | 3.4558 mL | |
| 10 mM | 0.1728 mL | 0.8639 mL | 1.7279 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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