ArticleJournal of medicinal chemistry2011
Discovery, synthesis, and biological evaluation of novel SMN protein modulators.
Article in Journal of medicinal chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 43 citations in OpenAlex.
- A Novel Minor Groove Binder as a Potential Therapeutic Agent for Myotonic Dystrophy Type 1.ChemMedChem · 2021Article
- Electrophilic alkylation of arenes with 5-bromopyrimidine en route to 4-aryl-5-alkynylpyrimidines.RSC advances · 2020Article
- A redox-neutral synthesis of ketones by coupling of alkenes and amides.Nature communications · 2019Article
- Intraperitoneal delivery of a novel drug-like compound improves disease severity in severe and intermediate mouse models of Spinal Muscular Atrophy.Scientific reports · 2019Article
- Using Systems Biology and Mathematical Modeling Approaches in the Discovery of Therapeutic Targets for Spinal Muscular Atrophy.Advances in neurobiology · 2018Review
- Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers.Bioorganic & medicinal chemistry letters · 2017Article
- Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy.Journal of medicinal chemistry · 2017Article
- Small Molecules in Development for the Treatment of Spinal Muscular Atrophy.Journal of medicinal chemistry · 2016Review
- ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice.JCI insight · 2016Article
- Mechanistic principles of antisense targets for the treatment of spinal muscular atrophy.Future medicinal chemistry · 2015Review
- Assays for the identification and prioritization of drug candidates for spinal muscular atrophy.Assay and drug development technologies · 2014Review
- Systems biology investigation of cAMP modulation to increase SMN levels for the treatment of spinal muscular atrophy.PloS one · 2014Article
- Phenotypic screens as a renewed approach for drug discovery.Drug discovery today · 2013Review
- The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models.Human molecular genetics · 2013Article
- Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds.EMBO molecular medicine · 2013Article
- Article
- A cell system for phenotypic screening of modifiers of SMN2 gene expression and function.PloS one · 2013Article
- SMN-inducing compounds for the treatment of spinal muscular atrophy.Future medicinal chemistry · 2012Review
- Firefly luciferase in chemical biology: a compendium of inhibitors, mechanistic evaluation of chemotypes, and suggested use as a reporter.Chemistry & biology · 2012Article
- Identification of novel compounds that increase SMN protein levels using an improved SMN2 reporter cell assay.Journal of biomolecular screening · 2012Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting the expression or function of survival motor neuron protein (SMN) due to the homozygous deletion or rare point mutations in the survival motor neuron gene 1 (SMN1). The human genome includes a second nearly identical gene called SMN2 that is retained in SMA. SMN2 transcripts undergo alternative splicing with reduced levels of SMN. Up-regulation of SMN2 expression, modification of its splicing, or inhibition of proteolysis of the truncated protein derived from SMN2 have been discussed as potential therapeutic strategies for SMA. In this manuscript, we detail the discovery of a series of arylpiperidines as novel modulators of SMN protein. Systematic hit-to-lead efforts significantly improved potency and efficacy of the series in the primary and orthogonal assays. Structure-property relationships including microsomal stability, cell permeability, and in vivo pharmacokinetics (PK) studies were also investigated. We anticipate that a lead candidate chosen from this series may serve as a useful probe for exploring the therapeutic benefits of SMN protein up-regulation in SMA animal models and a starting point for clinical development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.