title: Small Molecules in Development for the Treatment of Spinal Muscular Atrophy.
abstract: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease resulting from pathologically low levels of survival motor neuron (SMN) protein. The majority of mRNA from the SMN2 allele undergoes alternative splicing and excludes critical codons, causing an SMN protein deficiency. While there is currently no FDA-approved treatment for SMA, early therapeutic efforts have focused on testing repurposed drugs such as phenylbutyrate (2), valproic acid (3), riluzole (6), hydroxyurea (7), and albuterol (9), none of which has demonstrated clinical effectiveness. More recently, clinical trials have focused on novel small-molecule compounds identified from high-throughput screening and medicinal chemistry optimization such as olesoxime (11), CK-2127107, RG7800, LMI070, and RG3039 (17). In this paper, we review both repurposed drugs and small-molecule compounds discovered following medicinal chemistry optimization for the potential treatment of SMA.
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Alyssa N
authors.initials: AN
authors.lastname: Calder
authors.affiliation: Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States.
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Androphy
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hodgetts
mesh_terms: D002626:Chemistry, Pharmaceutical; D006801:Humans; D015394:Molecular Structure; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D018696:Neuroprotective Agents; D054852:Small Molecule Libraries