title: Discovery, synthesis, and biological evaluation of novel SMN protein modulators.
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.
authors.affiliation: NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Rockville, Maryland 20850, USA.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Xiao
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Steve
authors.initials: S
authors.lastname: Titus
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Cherry
authors.forename: Matthew
authors.initials: M
authors.lastname: Evans
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Androphy
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
mesh_terms: D017398:Alternative Splicing; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D015195:Drug Design; D005091:Exons; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D013329:Structure-Activity Relationship; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism*; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D010880:Piperidines; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D013830:Thiadiazoles; D013844:Thiazoles; D049409:Luciferases, Firefly