NVS-SM1

• CAT Number: I001984
• CAS Number: 1562338-42-4
• Molecular Formula: C₂₂H₂₇N₅O₂
• Molecular Weight: 393.49
• Purity: ≥95%
• Synonyms: Branaplam; LMI 070; LMI070; NVS-SM1
• Target: RNA splicing
• Solubility: DMSO: ≤ 6.12 mg/mL
• Storage: Store at -20C
• IUPAC Name: (6E)-3-(1H-pyrazol-4-yl)-6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)oxy-1H-pyridazin-6-ylidene]cyclohexa-2,4-dien-1-one
• InChI: 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/h5-9,12-13,16,25,27H,10-11H2,1-4H3,(H,23,24)/b18-17+
• InChIKey: YIFFDXMJVNKGBL-ISLYRVAYSA-N
• SMILES: CC1(CC(CC(N1)(C)C)OC2=NNC(=C3C=CC(=CC3=O)C4=CNN=C4)C=C2)C

Branaplam(cas 1562338-42-4), also known as  NVS-SM or LMI070, is a highly potent, selective and orally active small molecule SMN2 splicing modulator. Branaplam shows high plasma exposure, good bioavailability and, notably, good distribution to the brain, a primary target tissue NVS-SM1 exhibits efficacy at lower doses and exposures. NVS-SM1 shows robust activity across disease-relevant induced pluripotent stem cell (iPSc)-derived neurons. 

Overview of Clinical Research

Originator: Novartis
Class: Cyclohexanes; Pyrazoles; Pyridazines; Small molecules
Mechanism of Action: Survival of motor neuron 2 protein modulators
Orphan Drug Status: No
New Molecular Entity: Yes

Reference

1. Nat Chem Biol. 2015 Jul;11(7):511-7. doi: 10.1038/nchembio.1837. Epub 2015 Jun 1.
SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice.
Palacino J(1), Swalley SE(1), Song C(1), Cheung AK(1), Shu L(1), Zhang X(1), Van Hoosear M(1), Shin Y(1), Chin DN(1), Keller CG(2), Beibel M(2), Renaud NA(1), Smith TM(1), Salcius M(1), Shi X(1), Hild M(1), Servais R(1), Jain M(1), Deng L(1), Bullock C(1), McLellan M(1), Schuierer S(2), Murphy L(1), Blommers MJ(2), Blaustein C(1), Berenshteyn F(1), Lacoste A(1), Thomas JR(1), Roma G(2), Michaud GA(1), Tseng BS(1), Porter JA(1), Myer VE(1), Tallarico JA(1), Hamann LG(1), Curtis D(1), Fishman MC(1), Dietrich WF(1), Dales NA(1), Sivasankaran R(1).
Author information:
(1)Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA. (2)Novartis Institutes for Biomedical Research, Forum 1, Basel, Switzerland.
Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5/' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.