RG7800 (also known as RG-7800; RO6885247) is a potent and selective survival motor neuron 2 (SMN2) splicing modifier, which is currently being studies in human clinical trials for the treatment of Spinal Muscular Atrophy (SMA). The survival of motor neuron (SMN1) gene mutation or deletion is the genetic disorder known as SMA. It affects one out of every 10,000 live births, and in its most severe forms, it is linked to a high rate of mortality for children. Excellent pharmacokinetic and in vivo efficaciousness, along with a positive safety profile, characterize RG7800. In the brains of transgenic SMA model mice, RG7800 corrects alternative splicing of the human SMN2 gene, increasing the amount of SMN protein.

Physicochemical Properties

Molecular Formula	C24H28N6O
Molecular Weight	416.518724441528
Exact Mass	416.23
Elemental Analysis	C, 69.21; H, 6.78; N, 20.18; O, 3.84
CAS #	1449598-06-4
Related CAS #	1449598-06-4
PubChem CID	89741565
Appearance	Off-white to yellow solid powder
LogP	1.6
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	3
Heavy Atom Count	31
Complexity	865
Defined Atom Stereocenter Count	0
InChi Key	GYFRQCMDLBNZSF-UHFFFAOYSA-N
InChi Code	InChI=1S/C24H28N6O/c1-5-19-22-11-21(27-30(22)13-16(3)25-19)20-12-23(31)29-14-18(10-15(2)24(29)26-20)17-6-8-28(4)9-7-17/h10-14,17H,5-9H2,1-4H3
Chemical Name	2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-7-(1-methylpiperidin-4-yl)pyrido[1,2-a]pyrimidin-4-one
Synonyms	RG7800; RO-6885247; RG-7800; RO6885247; RG 7800; RO 6885247
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)

Biological Activity

ln Vitro	RG7800 stimulates alternative splicing of the SMN2 mRNA, which raises the amount of SMN protein. It has been demonstrated that RG7800 encourages the inclusion of exon 7 in SMN2 mRNA, producing full-length mRNA in vitro using fibroblasts from a patient with SMA type I[1].
ln Vivo	RG7800 indicates that the drug has a good oral bioavailability and a favorable pharmacokinetic profile in both rats and cynomolgus monkeys. Treatment with RG7800 clearly increases the levels of SMN protein in the SMA mouse model in a dose-dependent manner. Beginning at the low dose of 0.3/1 mg/kg, mice treated with RG7800 show a dose-dependent increase in survival. Approximately 80–90% of participants in the middle and high dose groups (1/3 and 3/10 mg/kg, respectively) survive past PND50/PND60 and have significantly increased body weight at the end of the study. It is possible that RG7800 corrects alternative splicing of the human SMN2 gene in the brains of transgenic SMA model mice, increasing the amount of SMN protein in the brain, by including exon 7 to produce FL mRNA, which corrects SMN2 splicing in a dose-dependent manner[1].
Animal Protocol	Mice: Oral administration of Compounds (RG7800) at three distinct doses (1, 3, and 10 mg/kg) is carried out once daily (qd) for ten days. Mice tissues are taken an hour after the last dose, and the amount of SMN protein in the brain and quadriceps muscle is measured[1].
References	[1]. Specific Correction of Alternative Survival Motor Neuron 2 Splicing by Small Molecules: Discovery of a Potential Novel Medicine To Treat Spinal Muscular Atrophy. J Med Chem. 2016 Jul 14;59(13):6086-100.

Solubility Data

Solubility (In Vitro)

Ethanol: ~2.5 mg/mL (~6.0 mM) DMSO: ~1.4 mg/mL (~3.4 mM) H2O: ~1.3 mg/mL (~3.0 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	2.4008 mL	12.0042 mL	24.0085 mL
	5 mM	0.4802 mL	2.4008 mL	4.8017 mL
	10 mM	0.2401 mL	1.2004 mL	2.4008 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.