| Identification | Back Directory | [Name]
Phenol, 2-[6-[methyl(2,2,6,6-tetramethyl-4-piperidinyl)amino]-3-pyridazinyl]-5-(1H-pyrazol-4-yl)- | [CAS]
1562333-92-9 | [Synonyms]
NVS-SM2
Phenol, 2-[6-[methyl(2,2,6,6-tetramethyl-4-piperidinyl)amino]-3-pyridazinyl]-5-(1H-pyrazol-4-yl)- | [Molecular Formula]
C23H30N6O | [MDL Number]
MFCD34469206 | [MOL File]
1562333-92-9.mol | [Molecular Weight]
406.52 |
| Chemical Properties | Back Directory | [Boiling point ]
673.3±55.0 °C(Predicted) | [density ]
1.162±0.06 g/cm3(Predicted) | [form ]
Solid | [pka]
8.03±0.40(Predicted) | [color ]
Off-white to light yellow |
| Hazard Information | Back Directory | [Uses]
NVS-SM2 is a potent, orally active and brain-penetrant SMN2 splicing enhancer with an EC50 of 2 nM for SMN. NVS-SM2 enhances U1-pre-mRNA association. NVS-SM2 promotes exon 7 inclusion and restores normal survival motor neuron (SMN) protein expression. NVS-SM2 can be used for spinal muscular atrophy (SMA) research[1][2]. | [Biological Activity]
NVS-SM2 is a potent, orally active and brain-penetrant SMN2 splicing enhancer with an EC50 of 2 nM for SMN. NVS-SM2 enhances U1-pre-mRNA association. NVS-SM2 promotes exon 7 inclusion and restores normal survival motor neuron (SMN) protein expression. NVS-SM2 can be used for spinal muscular atrophy (SMA) research[1][2].
For NVS-SM2, 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[1].
NVS-SM2 (0.1-1 mg/kg; s.c.; for 30 days) treatment extends survival in a severe SMA mouse model[2]. Pharmacokinetic analysis demonstrate that NVS-SM2 is readily available in the brain after IV and oral (PO) administration in mouse and rat with Tmax of 3 h after PO with 3 mg/kg in mice, and treatment induced a 1.5-fold increase in SMN protein levels in the mouse brain[1]. | [in vivo]
NVS-SM2 (0.1-1 mg/kg; s.c.; for 30 days) treatment extends survival in a severe SMA mouse model[2].
Pharmacokinetic analysis demonstrate that NVS-SM2 is readily available in the brain after IV and oral (PO) administration in mouse and rat with Tmax of 3 h after PO with 3 mg/kg in mice, and NVS-SM2 treatment induces a 1.5-fold increase in SMN protein levels in the mouse brain[1]. | Animal Model: | Severe SMA mice[2] | | Dosage: | 0.1 mg/kg and 1 mg/kg
| | Administration: | Subcutaneous injection; daily from day 2 to day 15, followed by every other day until day 30 | | Result: | Extended survival in a severe SMA mouse model. |
| [References]
[1]. James Palacino, et al. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat Chem Biol. 2015 Jul;11(7):511-7. [2]. Anne Rietz, et al. Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy. Life Sci Alliance. 2020 Nov 24;4(1):e202000889. |
|
|