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Branaplam diHCl (LMI-070 dihydrochloride; NVS-SM1) is a potent, orally bioactive, small-molecule enhancer of SMN2 (survival of motor neuron-2) splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. The SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex form a transient double-strand RNA structure, which is stabilized through a molecular mechanism. In a manner distinct from constitutive recognition, U1 snRNP increases its binding affinity to the 5' splice site in a sequence-specific manner. This novel mechanism shows that sequence-selective splice modulation via small molecules is feasible and may be used to treat other splicing disorders.
Branaplam diHCl (CAS 1562338-39-9) is a small molecule that promotes survival of spinal muscular atrophy (SMA) motor neurons by modulating SMN2 splicing. It is an orally active compound that increases the production of full-length SMN protein. The compound has been investigated for the treatment of spinal muscular atrophy and other neurodegenerative diseases. However, specific IC50 values and detailed activity data are not extensively reported in the available literature.
| Targets |
Branaplam diHCl targets the SMN2 gene splicing mechanism. Spinal muscular atrophy is caused by mutations in the SMN1 gene, leading to deficiency of the survival motor neuron (SMN) protein. SMN2 is a paralogous gene that produces predominantly truncated, unstable SMN protein due to skipping of exon 7. Branaplam promotes the inclusion of exon 7 in SMN2 mRNA, increasing the production of full-length, functional SMN protein. By increasing SMN protein levels, the compound promotes the survival of motor neurons.
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| ln Vitro |
Branaplam HCl (LMI-070 hydrochloride; NVS-SM1) treatment alters the levels of 175 genes in human fibroblasts[1].
In vitro, Branaplam diHCl promotes the inclusion of exon 7 in SMN2 mRNA and increases full-length SMN protein levels in cells derived from SMA patients. It shows efficacy in cellular models of SMA by promoting motor neuron survival. However, specific IC50 values and detailed in vitro activity data are not extensively reported in the available literature. |
| ln Vivo |
Branaplam HCl (LMI-070 hydrochloride; NVS-SM1) (3, 10, 30 mg/kg; oral) hydrochloride causes dose-dependent increases in SMN2-FL transcript and SMN protein in brain and spinal cord[1]. Branaplam hydrochloride (1 mg/kg IV; 3 mg/kg PO) has an AUC of 3.03 μM•h and a CL of 25 mL/min/kg[2]. In the brains of C/+ mice, a single oral dose of 30 mg/kg of Branaplam hydrochloride causes a prominent and long-lasting increase in SMN protein for as long as 160 hours[1]. Branaplam hydrochloride (oral; 0.03, 0.1, 0.3, 1, 3 mg/kg) increases body weight and prolongs life in SMNΔ7 mice[1].
In vivo, Branaplam diHCl has been studied in animal models of SMA. As an orally active compound, it has shown efficacy in increasing SMN protein levels and improving survival and motor function in SMA mouse models. The compound has been investigated in clinical trials for the treatment of SMA. However, specific efficacy data and dosing regimens are not extensively detailed. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for Branaplam diHCl are not applicable, as the compound acts by modulating RNA splicing rather than binding to a specific enzyme or receptor. The compound's activity is assessed by measuring SMN2 exon 7 inclusion using RT-PCR or by measuring full-length SMN protein levels by Western blotting or ELISA in SMA patient-derived cells.
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| Cell Assay |
In vitro cellular assays for Branaplam diHCl use fibroblast or lymphoblastoid cell lines derived from SMA patients. Cells are cultured in appropriate media and treated with various concentrations of the compound (0.001-10 μM) for 24-72 hours. SMN2 exon 7 inclusion is assessed by RT-PCR. SMN protein levels are measured by Western blotting or ELISA. Motor neuron survival is assessed in differentiated motor neuron cultures.
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| Animal Protocol |
In vivo animal studies with Branaplam diHCl use mouse models of SMA (e.g., SMNΔ7 mice). Mice are treated with the compound orally at doses of 1-30 mg/kg daily for several weeks. Survival, body weight, motor function (rotarod, grip strength), and SMN protein levels in tissues are assessed. Histological analysis of spinal cord and muscle is performed.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Branaplam diHCl: The compound is orally active, indicating good oral bioavailability. Specific PK parameters such as Cmax, Tmax, AUC, half-life, and tissue distribution are not extensively reported. The compound is expected to cross the blood-brain barrier to reach the central nervous system.
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| Toxicity/Toxicokinetics |
The toxicity profile of Branaplam diHCl is not extensively reported. As a compound that modulates RNA splicing, potential toxicities may include off-target effects on other splicing events. The compound is for research use only and not for human therapeutic use. Standard toxicity studies would include acute and subchronic toxicity in rodents.
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| References |
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| Additional Infomation |
Branaplam diHCl (CAS 1562338-39-9) is a small molecule that promotes survival of SMA motor neurons by modulating SMN2 splicing and increasing full-length SMN protein production. It is orally active and has been investigated for the treatment of spinal muscular atrophy. The compound is available for research purposes only.
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| Molecular Formula |
C22H28CLN5O2
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| Molecular Weight |
429.94
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| Exact Mass |
429.19
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| Elemental Analysis |
C, 61.46; H, 6.56; Cl, 8.25; N, 16.29; O, 7.44
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| CAS # |
1562338-39-9
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| Related CAS # |
1562338-42-4; 1562338-39-9 (HCl)
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| PubChem CID |
135565041
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
30
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| Complexity |
541
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
XJIMIVJABPKGIY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H27N5O2.ClH/c1-21(2)10-16(11-22(3,4)27-21)29-20-8-7-18(25-26-20)17-6-5-14(9-19(17)28)15-12-23-24-13-15;/h5-9,12-13,16,27-28H,10-11H2,1-4H3,(H,23,24);1H
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| Chemical Name |
5-(1H-pyrazol-4-yl)-2-[6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazin-3-yl]phenol;hydrochloride
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| Synonyms |
Branaplam HCl; Branaplam hydrochloride; LMI-070 hydrochloride; LMI 070 HCl; LMI070 HCl; LMI-070 HCl
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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) |
H2O : ~200 mg/mL (~465.18 mM)
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| 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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3259 mL | 11.6295 mL | 23.2591 mL | |
| 5 mM | 0.4652 mL | 2.3259 mL | 4.6518 mL | |
| 10 mM | 0.2326 mL | 1.1630 mL | 2.3259 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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