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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
MeSH terms
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Anilides / pharmacokinetics
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Anilides / pharmacology*
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Anilides / therapeutic use
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Area Under Curve
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Benzamides / pharmacokinetics
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Benzamides / pharmacology*
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Benzamides / therapeutic use
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Cell Line
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Drug Discovery
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Half-Life
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Humans
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Isoxazoles / pharmacokinetics
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Isoxazoles / pharmacology*
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Isoxazoles / therapeutic use
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Molecular Probes*
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Muscular Atrophy, Spinal / therapy*
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Protein Processing, Post-Translational*
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Protein Stability
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Quinolones / pharmacokinetics
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Quinolones / pharmacology*
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Quinolones / therapeutic use
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Structure-Activity Relationship
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Survival of Motor Neuron 1 Protein / metabolism*
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology*
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Thiazoles / therapeutic use
Substances
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3-chloro-4-fluoro-N-(5-(1-hydroxycyclobutyl)thiazol-2-yl)benzamide
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Anilides
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Benzamides
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Isoxazoles
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LDN-75654
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LDN-76070
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Molecular Probes
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Quinolones
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Survival of Motor Neuron 1 Protein
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Thiazoles