Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C22H27N5O2 |
| Molecular Weight | 393.4821 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CC1(C)CC(CC(C)(C)N1)OC2=NN=C(C=C2)C3=C(O)C=C(C=C3)C4=CNN=C4
InChI
InChIKey=STWTUEAWRAIWJG-UHFFFAOYSA-N
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)
LMI-070 is an experimental compound being developed by Novartis Pharma as a treatment for spinal muscular atrophy (SMA). It is a small-molecule drug which modifies alternative splicing of the SMN2 gene, bringing about increased levels of SMN protein. LMI-070 originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, LMI-070 treatment increased full-length SMN RNA and protein levels, and extended survival. LMI-070 is taken orally, usually in a liquid form once a week. It is in phase II clinical trial.
Originator
Approval Year
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
9.1 ng/mL |
0.321 mg/kg single, oral dose: 0.321 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
LMI-070 plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN |
|
18.6 ng/mL |
0.654 mg/kg single, oral dose: 0.654 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
LMI-070 plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN |
|
55.6 ng/mL |
1.39 mg/kg single, oral dose: 1.39 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
LMI-070 plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN |
|
53.2 ng/mL |
2.49 mg/kg single, oral dose: 2.49 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
LMI-070 plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN |
|
72.4 ng/mL |
2.94 mg/kg single, oral dose: 2.94 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
LMI-070 plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
378 ng × h/mL |
0.321 mg/kg single, oral dose: 0.321 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
LMI-070 plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN |
|
892 ng × h/mL |
0.654 mg/kg single, oral dose: 0.654 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
LMI-070 plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN |
|
1820 ng × h/mL |
1.39 mg/kg single, oral dose: 1.39 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
LMI-070 plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN |
|
3310 ng × h/mL |
2.49 mg/kg single, oral dose: 2.49 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
LMI-070 plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN |
|
3800 ng × h/mL |
2.94 mg/kg single, oral dose: 2.94 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
LMI-070 plasma | Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: UNKNOWN |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA). | 2018-12-27 |
|
| Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2-4 (SPACE trial). | 2018-07-30 |
|
| Small Molecules in Development for the Treatment of Spinal Muscular Atrophy. | 2016-11-23 |
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| Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
620117
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FDA ORPHAN DRUG |
773320
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EU-Orphan Drug |
EU/3/18/2010
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135565042
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DB14918
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100000174622
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Branaplam
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JK-244
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BRANAPLAM
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PRIMARY | LMI070 (NVS-SM1) is a highly potent, selective and orally active small molecule SMN2 splicing modulator.Target: RNA splicingin vitro: NVS-SM1 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.in vivo : To evaluate the efficacy of NVS-SM1, we used the SMN.DELTA.7 mouse model, which displays a severe phenotype. In the specific colony used for this study, death typically occurs before postnatal day 15. We were pleased to observe that, in addition to a dose-dependent elevation of SMN protein in the brain, oral administration of NVS-SM1 improved body weight and extended lifespan, with 50% of the animals in the 1 mg per kg body weight group and 62% of animals in the 3 mg per kg body weight group showing increased survival. | ||
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10380
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DTXSID801337133
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C174824
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1562338-42-4
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P12R69543A
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ACTIVE MOIETY
SALT/SOLVATE (PARENT)
