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Purity: ≥98%
Branaplam HCl (LMI-070 HCl; 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 transient double-strand RNA structure created by the U1 small nuclear ribonucleic protein (snRNP) complex and SMN2 pre-mRNA is stabilized as the molecular mechanism of action. Separate from constitutive recognition, the binding affinity of U1 snRNP to the 5' splice site is enhanced in a sequence-specific manner. This novel mechanism highlights the viability of sequence-selective splice modulation mediated by small molecules and the possibility of applying this tactic to other splicing disorders.
| Targets |
Branaplam (LMI070; NVS-SM1) hydrochloride treatment alters the levels of 175 genes in human fibroblasts[1].
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| ln Vitro |
Branaplam (LMI070; NVS-SM1) hydrochloride treatment alters the levels of 175 genes in human fibroblasts[1].
Compound 2 (hit) activated SMN2 reporter by 1700% over DMSO control with EC50 = 3.5 µM in NSC34 motor neuron cell line expressing SMN2 minigene reporter. Compound 2 increased SMN protein levels in mouse SMN ELISA assay (EC50 = 0.6 µM, 2.5-fold increase) and in human patient-derived fibroblasts (1.5-fold increase). Branaplam (compound 1) increased SMN protein in SMN ELISA with EC50 = 0.020 µM and 3.6-fold induction. hERG binding assay: Branaplam showed hERG IC50 = 6.3 µM (radioligand binding with [³H]dofetilide). [1] |
| 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 C/+ mice, a single oral dose of 30 mg/kg of Branaplam hydrochloride causes a notable and long-lasting increase in SMN protein in the brain for up to 160 hours[1]. Branaplam (oral; 0.03, 0.1, 0.3, 1, 3 mg/kg) hydrochloride increases body weight and prolongs lifespan in n SMNΔ7 mice[1].
Compound 8 (tool compound) dosed orally in SMN delta7 mice (postnatal day 3, daily) increased brain SMN protein in a dose-dependent manner (1–30 mg/kg). Significant survival extension was observed at 3 and 10 mg/kg, with reduced survival at 30 mg/kg suggesting tolerability issues. Branaplam (1) dosed orally in SMN delta7 mice showed dose-dependent SMN protein elevation in brain (statistically significant even at 0.3 mg/kg), improved body weight, and extended lifespan. Durability of effect was demonstrated by continued dosing from day 36 to 49. In SMN C/+ mice, Branaplam (1) significantly increased brain SMN protein at 10 mg/kg after 5 days, while compound 19 required 30 mg/kg for comparable effect. [1] |
| Enzyme Assay |
hERG radioligand binding assay was performed using [³H]dofetilide to determine IC50 values for hERG channel inhibition. The assay measures displacement of radiolabeled dofetilide from hERG channels expressed in cell membranes. [1]
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| Cell Assay |
SMN2 reporter assay: NSC34 motor neuron cell line expressing SMN2 minigene reporter constructs (one for exon 7 inclusion, one for exon 7 exclusion) was used. Luciferase activity was measured to assess splicing modulation.
SMN ELISA: Mouse myoblasts (SMNA7) or patient-derived fibroblasts were treated with compounds, and SMN protein levels were quantified using ELISA. Dose-response curves were generated to determine EC50 and fold induction. [1] |
| Animal Protocol |
SMN delta7 mouse model: Mice (severe SMA phenotype) were dosed orally with compounds (e.g., compound 8 or Branaplam) daily starting at postnatal day 3. Doses ranged from 0.3 to 30 mg/kg. Brain and spinal cord tissues were collected for SMN protein analysis by ELISA. Survival and body weight were monitored.
SMN C/+ mouse model: Mice were dosed orally for 5 days, and brain SMN protein levels were measured by ELISA. Pharmacokinetic studies in mice/rats: Compounds were administered intravenously (1 mg/kg) or orally (3–10 mg/kg). Blood and brain samples were collected at various time points for LC-MS/MS analysis to determine AUC, clearance, half-life, and brain-to-plasma ratios. Formulations included 10% 0.1 N HCl, 10% propylene glycol, 25% Solutol HS-15, and citrate buffer. [1] |
| ADME/Pharmacokinetics |
Compound 2: Mouse clearance (CL) = 113 mL/min/kg, oral bioavailability = 18%, low brain exposure (brain AUC below mass level). Compound 3: Increased bioavailability (100%), brain AUC = 17.4 µM·h. Branaplam (1): Rat clearance (CL) = 25 mL/min/kg, oral bioavailability = 63%, brain AUC = 3.03 µM·h, brain-to-plasma ratio (free) = 0.5–3.0, rat plasma protein binding = 73%. Brain exposure was predicted using the MDCK-MDR1 cell permeability assay. [1]
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| Toxicity/Toxicokinetics |
hERG inhibition: Branaplam hERG IC50 = 6.3 µM (an improvement over earlier analogs). Rat plasma protein binding was 73% (Branaplam). [1]
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| References |
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| Additional Infomation |
Branaplam is a small molecule splicing regulator discovered through phenotypic screening. It stabilizes the interaction between U1-snRNP and SMN2 precursor mRNA, promotes exon 7 insertion, and thus increases the expression of full-length SMN protein.
It has oral bioavailability and has shown efficacy in a mouse model of severe SMA, supporting its entry into clinical trials for type 1 SMA. Clinical trial NCT02268552 is a phase I study for children with type 1 SMA. [1] |
| 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 # |
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| PubChem CID |
135565041
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
0
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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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| SMILES |
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 |
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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. |
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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) |
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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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05111249 | Completed | Drug: Branaplam Drug: Placebo |
Early Manifest Huntington Disease |
Novartis Pharmaceuticals | December 8, 2021 | Phase 2 |
| NCT02268552 | Completed | Drug: branaplam | Spinal Muscular Atrophy | Novartis Pharmaceuticals | April 2, 2015 | Phase 1 Phase 2 |
| NCT05330286 | Terminated | Drug: LMI070 | Healthy Volunteers | Novartis Pharmaceuticals | April 13, 2022 | Phase 1 |
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