Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)

J Med Chem. 2018 Aug 9;61(15):6501-6517. doi: 10.1021/acs.jmedchem.8b00741. Epub 2018 Jul 25.


SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated, systemically distributed small molecules to increase levels of functional SMN protein. Compound 2 was the first SMN2 splicing modifier tested in clinical trials in healthy volunteers and SMA patients. It was safe and well tolerated and increased SMN protein levels up to 2-fold in patients. Nevertheless, its development was stopped as a precautionary measure because retinal toxicity was observed in cynomolgus monkeys after chronic daily oral dosing (39 weeks) at exposures in excess of those investigated in patients. Herein, we describe the discovery of 1 (risdiplam, RG7916, RO7034067) that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is undergoing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages with SMA.

MeSH terms

  • Animals
  • Azo Compounds / adverse effects
  • Azo Compounds / pharmacology*
  • Azo Compounds / therapeutic use
  • Drug Discovery*
  • Humans
  • Muscular Atrophy, Spinal / drug therapy*
  • Muscular Atrophy, Spinal / genetics*
  • Pyrimidines / adverse effects
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • RNA Splicing / drug effects*
  • Safety
  • Survival of Motor Neuron 2 Protein / genetics*


  • Azo Compounds
  • Pyrimidines
  • Survival of Motor Neuron 2 Protein
  • Risdiplam