RG3039 (also known as PF-06687859; PF 06687859), a member of a chemical series that was identified and optimized using an SMN2 promoter screen, is a novel, potent, orally bioavailable and brain-penetrant DcpS (decapping scavenger enzyme) inhibitor with an IC50 of 0.069 nM. In a mouse model of spinal muscular atrophy, it increases motor function and lengthens survival (SMA). Although it is a strong inhibitor of the mRNA decapping scavenger enzyme (DcpS), it is unknown how DcpS inhibition benefits medicine. It is anticipated that the dibasic lipophilic molecule RG3039 will gather in lysosomes.
Physicochemical Properties
| Molecular Formula | C21H23N5OCL2 |
| Molecular Weight | 432.34622 |
| Exact Mass | 431.127 |
| Elemental Analysis | C, 58.34; H, 5.36; Cl, 16.40; N, 16.20; O, 3.70 |
| CAS # | 1005504-62-0 |
| PubChem CID | 53258905 |
| Appearance | White to off- white solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 648.1±65.0 °C at 760 mmHg |
| Flash Point | 345.8±34.3 °C |
| Vapour Pressure | 0.0±1.9 mmHg at 25°C |
| Index of Refraction | 1.682 |
| LogP | 4.25 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 29 |
| Complexity | 511 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | NC1=NC(N)=C2C(OCC3CCN(CC4=C(Cl)C=CC=C4Cl)CC3)=CC=CC2=N1 |
| InChi Key | MNLHFGXIUJNDAF-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C21H23Cl2N5O/c22-15-3-1-4-16(23)14(15)11-28-9-7-13(8-10-28)12-29-18-6-2-5-17-19(18)20(24)27-21(25)26-17/h1-6,13H,7-12H2,(H4,24,25,26,27) |
| Chemical Name | 5-[[1-[(2,6-dichlorophenyl)methyl]piperidin-4-yl]methoxy]quinazoline-2,4-diamine |
| Synonyms | PF06687859; PF 06687859; PF-06687859; RG 3039; RG3039; RG-3039 |
| HS Tariff Code | 2934.99.03.00 |
| 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) |
Biological Activity
| Targets | DcpS ( IC50 = 4.2 nM ); DcpS ( IC90 = 40 nM ) |
| ln Vitro | RG3039 is a binary lipophilic compound that has the potential to build up in lysosomes [1]. |
| ln Vivo | In two SMA mouse models (Taiwan 5058 Hemi and 2B/SMA mice) of differing disease severity, RG3039 can prolong longevity and enhance function, with a beneficial effect on optic neuropathy. RG3039 demonstrated a >600% survival advantage from the commencement of P4 (median 18 days to >112 days) in a 2B/- SMA mouse model, underscoring the significance of early intervention [2]. When RG3039 reaches the tissues of the central nervous system, it significantly suppresses the enzymatic activity of DcpS while only weakly inducing the expression of SMN or small ribonucleoprotein complexing. Motor neuron soma, neuronal synaptic innervation and function, and surgical size were all improved in RG3039-treated SMA samples. These changes were correlated with dose-dependent increases in quarter, body weight, and motor performance. connected. Additionally, conditional SMA electrodes' drying rate is accelerated by RG3039 [3]. |
| Animal Protocol | Mice: Intraperitoneal (i.p.) injections of RG3039 are administered to mice commencing on postnatal day 1 (P1), which is the day of birth. At P4, all treated litters with a maximum of six pups are culled. Starting with P1, daily weights and righting-time are established. The ambulation index runs from P13 to P23. Two trials of 60 seconds are used to calculate a compilation score[3]. |
| References |
[1]. Gopalsamy A, et al. Design of Potent mRNA Decapping Scavenger Enzyme (DcpS) Inhibitors with Improved Physicochemical Properties To Investigate the Mechanism of Therapeutic Benefit in Spinal Muscular Atrophy (SMA). J Med Chem. 2017 Apr 13;60(7):3094-3108. [2]. Gogliotti RG, et al. The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models. Hum Mol Genet. 2013 Oct 15;22(20):4084-101. [3]. Van Meerbeke J, et al. The DcpS inhibitor RG3039 improves motor function in SMA mice. Hum Mol Genet. 2013 Oct 15;22(20):4074-83 |
Solubility Data
| Solubility (In Vitro) |
DMSO: 3~5 mg/mL (6.9~11.6 mM) H2O: ~1 mg/mL (~2.3 mM) |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3129 mL | 11.5647 mL | 23.1294 mL | |
| 5 mM | 0.4626 mL | 2.3129 mL | 4.6259 mL | |
| 10 mM | 0.2313 mL | 1.1565 mL | 2.3129 mL |