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MedKoo Cat#: 526827 | Name: Branaplam free base
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Branaplam, also known as NVS-SM1 and LMI-070, is a highly potent, selective and orally active small molecule SMN2 splicing modulator as a potential treatment for SMA Type 1 (Spinal Muscular Atrophy) .NVS-SM1 works by increasing the amount of functional SMN protein produced by the “back-up” gene, SMN2, through modifying its splicing.

Chemical Structure

Branaplam free base
Branaplam free base
CAS#1562338-42-4 (free base)

Theoretical Analysis

MedKoo Cat#: 526827

Name: Branaplam free base

CAS#: 1562338-42-4 (free base)

Chemical Formula: C22H27N5O2

Exact Mass: 393.2165

Molecular Weight: 393.49

Elemental Analysis: C, 67.15; H, 6.92; N, 17.80; O, 8.13

Price and Availability

Size Price Availability Quantity
5mg USD 90.00 Ready to ship
10mg USD 150.00 Ready to ship
25mg USD 250.00 Ready to ship
50mg USD 450.00 Ready to ship
100mg USD 750.00 Ready to ship
200mg USD 1,250.00 Ready to ship
500mg USD 2,650.00 Ready to ship
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Related CAS #
1562338-42-4 (free base) 1562338-39-9 (HCl) Branaplam mesylate
Synonym
NVS-SM1; NVS SM1; NVSSM1; LMI-070; LMI070; LMI 070; Branaplam
IUPAC/Chemical Name
5-(1H-pyrazol-4-yl)-2-[6-[(2,2,6,6-tetramethyl-4-piperidinyl)oxy]-3-pyridazinyl]-phenol
InChi Key
STWTUEAWRAIWJG-UHFFFAOYSA-N
InChi Code
InChI=1S/C22H27N5O2/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)
SMILES Code
OC1=CC(C2=CNN=C2)=CC=C1C3=NN=C(OC4CC(C)(C)NC(C)(C)C4)C=C3
Appearance
Solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Biological target:
Branaplam (LMI070) is a highly selective, small-molecule splicing modulators of survival motor neuron‑2 (SMN2) with an EC50 of 0.02 μM.
In vitro activity:
In the cellular setting, it was observed that SMN protein levels remained elevated after compound treatment, which and suggests that SMN protein has a long half-life. Branaplam (LMI070; NVS-SM1) treatment induces changes in the levels of 175 genes in human fibroblasts. Reference: Nat Chem Biol. 2015 Jul;11(7):511-7. https://doi.org/10.1038/nchembio.1837
In vivo activity:
The C/+ SMA mouse model was employed. After oral administration, NVS-SM1 produced dose-dependent elevations of SMN2-FL transcript and SMN protein in brain and spinal cord (Fig. 2a,b), thus establishing translatability and a pharmacokinetic-pharmacodynamic relationship. Although it showed dose-responsive activity in the C/+ model (Fig. 2a,b), NVS-SM1 exhibited efficacy at lower doses and exposures. NVS-SM1 showed robust activity across disease-relevant induced pluripotent stem cell (iPSc)-derived neurons (Supplementary Fig. 2a,b). It was also demonstrated that the desired transcript response in SMA-type III PBMCs after NVS-SM1 treatment, suggesting that this readout could serve as a peripheral pharmacodynamic marker in the clinic (Supplementary Fig. 2c). A single, 30 mg per kg body weight oral dose of NVS-SM1 resulted in significant (P < 0.05) and durable SMN protein elevation in brain for up to 160 h (Fig. 2c). Reference: Nat Chem Biol. 2015 Jul;11(7):511-7. https://doi.org/10.1038/nchembio.1837
Solvent mg/mL mM
Solubility
DMSO 3.0 7.62
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 393.49 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol:
1. Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, Van Hoosear M, Shin Y, Chin DN, Keller CG, Beibel M, Renaud NA, Smith TM, Salcius M, Shi X, Hild M, Servais R, Jain M, Deng L, Bullock C, McLellan M, Schuierer S, Murphy L, Blommers MJ, Blaustein C, Berenshteyn F, Lacoste A, Thomas JR, Roma G, Michaud GA, Tseng BS, Porter JA, Myer VE, Tallarico JA, Hamann LG, Curtis D, Fishman MC, Dietrich WF, Dales NA, Sivasankaran R. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat Chem Biol. 2015 Jul;11(7):511-7. doi: 10.1038/nchembio.1837. Epub 2015 Jun 1. Erratum in: Nat Chem Biol. 2015 Sep;11(9):741. Erratum in: Nat Chem Biol. 2016 Apr;12(4):304. PMID: 26030728.
In vivo protocol:
1. Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, Van Hoosear M, Shin Y, Chin DN, Keller CG, Beibel M, Renaud NA, Smith TM, Salcius M, Shi X, Hild M, Servais R, Jain M, Deng L, Bullock C, McLellan M, Schuierer S, Murphy L, Blommers MJ, Blaustein C, Berenshteyn F, Lacoste A, Thomas JR, Roma G, Michaud GA, Tseng BS, Porter JA, Myer VE, Tallarico JA, Hamann LG, Curtis D, Fishman MC, Dietrich WF, Dales NA, Sivasankaran R. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat Chem Biol. 2015 Jul;11(7):511-7. doi: 10.1038/nchembio.1837. Epub 2015 Jun 1. Erratum in: Nat Chem Biol. 2015 Sep;11(9):741. Erratum in: Nat Chem Biol. 2016 Apr;12(4):304. PMID: 26030728. 2. Cheung AK, Hurley B, Kerrigan R, Shu L, Chin DN, Shen Y, O'Brien G, Sung MJ, Hou Y, Axford J, Cody E, Sun R, Fazal A, Fridrich C, Sanchez CC, Tomlinson RC, Jain M, Deng L, Hoffmaster K, Song C, Van Hoosear M, Shin Y, Servais R, Towler C, Hild M, Curtis D, Dietrich WF, Hamann LG, Briner K, Chen KS, Kobayashi D, Sivasankaran R, Dales NA. Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018 Dec 27;61(24):11021-11036. doi: 10.1021/acs.jmedchem.8b01291. Epub 2018 Dec 13. PMID: 30407821.
1: Childs-Disney JL, Yang X, Gibaut QMR, Tong Y, Batey RT, Disney MD. Targeting RNA structures with small molecules. Nat Rev Drug Discov. 2022 Oct;21(10):736-762. doi: 10.1038/s41573-022-00521-4. Epub 2022 Aug 8. PMID: 35941229; PMCID: PMC9360655. 2: Yu AM, Choi YH, Tu MJ. RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges. Pharmacol Rev. 2020 Oct;72(4):862-898. doi: 10.1124/pr.120.019554. PMID: 32929000; PMCID: PMC7495341. 3: Theil D, Valdez R, Darribat K, Doelemeyer A, Sivasankaran R, Hartmann A. Orally administered branaplam does not impact neurogenesis in juvenile mice, rats, and dogs. Biol Open. 2021 Oct 15;10(10):bio058551. doi: 10.1242/bio.058551. Epub 2021 Oct 28. PMID: 34528068; PMCID: PMC8565466. 4: Keller CG, Shin Y, Monteys AM, Renaud N, Beibel M, Teider N, Peters T, Faller T, St-Cyr S, Knehr J, Roma G, Reyes A, Hild M, Lukashev D, Theil D, Dales N, Cha JH, Borowsky B, Dolmetsch R, Davidson BL, Sivasankaran R. An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion. Nat Commun. 2022 Mar 3;13(1):1150. doi: 10.1038/s41467-022-28653-6. PMID: 35241644; PMCID: PMC8894458. 5: Krach F, Stemick J, Boerstler T, Weiss A, Lingos I, Reischl S, Meixner H, Ploetz S, Farrell M, Hehr U, Kohl Z, Winner B, Winkler J. An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington's disease patient neurons. Nat Commun. 2022 Nov 10;13(1):6797. doi: 10.1038/s41467-022-34419-x. PMID: 36357392; PMCID: PMC9649613. 6: Kirschner J, Butoianu N, Goemans N, Haberlova J, Kostera-Pruszczyk A, Mercuri E, van der Pol WL, Quijano-Roy S, Sejersen T, Tizzano EF, Ziegler A, Servais L, Muntoni F. European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy. Eur J Paediatr Neurol. 2020 Sep;28:38-43. doi: 10.1016/j.ejpn.2020.07.001. Epub 2020 Jul 9. PMID: 32763124; PMCID: PMC7347351. 7: Haniff HS, Knerr L, Chen JL, Disney MD, Lightfoot HL. Target-Directed Approaches for Screening Small Molecules against RNA Targets. SLAS Discov. 2020 Sep;25(8):869-894. doi: 10.1177/2472555220922802. Epub 2020 May 18. PMID: 32419578; PMCID: PMC7442623. 8: Cheung AK, Hurley B, Kerrigan R, Shu L, Chin DN, Shen Y, O'Brien G, Sung MJ, Hou Y, Axford J, Cody E, Sun R, Fazal A, Fridrich C, Sanchez CC, Tomlinson RC, Jain M, Deng L, Hoffmaster K, Song C, Van Hoosear M, Shin Y, Servais R, Towler C, Hild M, Curtis D, Dietrich WF, Hamann LG, Briner K, Chen KS, Kobayashi D, Sivasankaran R, Dales NA. Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018 Dec 27;61(24):11021-11036. doi: 10.1021/acs.jmedchem.8b01291. Epub 2018 Dec 13. PMID: 30407821. 9: Ottesen EW, Singh NN, Luo D, Kaas B, Gillette BJ, Seo J, Jorgensen HJ, Singh RN. Diverse targets of SMN2-directed splicing-modulating small molecule therapeutics for spinal muscular atrophy. Nucleic Acids Res. 2023 Apr 7:gkad259. doi: 10.1093/nar/gkad259. Epub ahead of print. PMID: 37026480. 10: Singh RN, Ottesen EW, Singh NN. The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy. Neurosci Insights. 2020 Nov 23;15:2633105520973985. doi: 10.1177/2633105520973985. PMID: 33283185; PMCID: PMC7691903. 11: Ramdas S, Servais L. New treatments in spinal muscular atrophy: an overview of currently available data. Expert Opin Pharmacother. 2020 Feb;21(3):307-315. doi: 10.1080/14656566.2019.1704732. PMID: 31973611. 12: Axford J, Sung MJ, Manchester J, Chin D, Jain M, Shin Y, Dix I, Hamann LG, Cheung AK, Sivasankaran R, Briner K, Dales NA, Hurley B. Use of Intramolecular 1,5-Sulfur-Oxygen and 1,5-Sulfur-Halogen Interactions in the Design of N- Methyl-5-aryl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-am ine SMN2 Splicing Modulators. J Med Chem. 2021 Apr 22;64(8):4744-4761. doi: 10.1021/acs.jmedchem.0c02173. Epub 2021 Apr 6. PMID: 33822618. 13: Das B, Murata A, Nakatani K. A small-molecule fluorescence probe ANP77 for sensing RNA internal loop of C, U and A/CC motifs and their binding molecules. Nucleic Acids Res. 2021 Sep 7;49(15):8462-8470. doi: 10.1093/nar/gkab650. PMID: 34358308; PMCID: PMC8421207. 14: Dangouloff T, Servais L. Clinical Evidence Supporting Early Treatment Of Patients With Spinal Muscular Atrophy: Current Perspectives. Ther Clin Risk Manag. 2019 Oct 2;15:1153-1161. doi: 10.2147/TCRM.S172291. PMID: 31632042; PMCID: PMC6778729. 15: Kant-Smits K, Bartels B, Asselman FL, Veldhoen ES, van Eijk RPA, van der Pol WL, Hulzebos EHJ. The RESISTANT study (Respiratory Muscle Training in Patients with Spinal Muscular Atrophy): study protocol for a randomized controlled trial. BMC Neurol. 2023 Mar 23;23(1):118. doi: 10.1186/s12883-023-03136-3. PMID: 36959618; PMCID: PMC10035150. 16: Ros LAA, Goedee HS, Franssen H, Asselman FL, Bartels B, Cuppen I, van Eijk RPA, Sleutjes BTHM, van der Pol WL, Wadman RI. Longitudinal prospective cohort study to assess peripheral motor function with extensive electrophysiological techniques in patients with Spinal Muscular Atrophy (SMA): the SMA Motor Map protocol. BMC Neurol. 2023 Apr 24;23(1):164. doi: 10.1186/s12883-023-03207-5. PMID: 37095427; PMCID: PMC10124000.

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