3 research outputs found
Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy
No full textThe underlying cause
of spinal muscular atrophy (SMA) is a deficiency
of the survival motor neuron (SMN) protein. Starting from hits identified
in a high-throughput screening campaign and through structure–activity
relationship investigations, we have developed small molecules that
potently shift the alternative splicing of the <i>SMN2</i> exon 7, resulting in increased production of the full-length SMN
mRNA and protein. Three novel chemical series, represented by compounds <b>9</b>, <b>14</b>, and <b>20</b>, have been optimized
to increase the level of SMN protein by >50% in SMA patient-derived
fibroblasts at concentrations of <160 nM. Daily administration
of these compounds to severe SMA Δ7 mice results in an increased
production of SMN protein in disease-relevant tissues and a significant
increase in median survival time in a dose-dependent manner. Our work
supports the development of an orally administered small molecule
for the treatment of patients with SMA
Discovery of Risdiplam, a Selective Survival of Motor Neuron‑2 (<i>SMN2</i>) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)
No full textSMA
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 <b>2</b> 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 <b>1</b> (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
Discovery of Risdiplam, a Selective Survival of Motor Neuron‑2 (<i>SMN2</i>) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)
No full textSMA
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 <b>2</b> 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 <b>1</b> (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
