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Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2017 Jun 08; Vol. 60 (11), pp. 4594-4610. Date of Electronic Publication: 2017 May 19. - Publication Year :
- 2017
-
Abstract
- Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.
- Subjects :
- Anilides pharmacokinetics
Anilides therapeutic use
Area Under Curve
Benzamides pharmacokinetics
Benzamides therapeutic use
Cell Line
Drug Discovery
Half-Life
Humans
Isoxazoles pharmacokinetics
Isoxazoles therapeutic use
Protein Stability
Quinolones pharmacokinetics
Quinolones therapeutic use
Structure-Activity Relationship
Thiazoles pharmacokinetics
Thiazoles therapeutic use
Anilides pharmacology
Benzamides pharmacology
Isoxazoles pharmacology
Molecular Probes
Muscular Atrophy, Spinal therapy
Protein Processing, Post-Translational
Quinolones pharmacology
Survival of Motor Neuron 1 Protein metabolism
Thiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 60
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28481536
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.6b01885