ABSTRACT
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.
Subject(s)
Azo Compounds/pharmacology , Drug Discovery , Muscular Atrophy, Spinal/drug therapy , Muscular Atrophy, Spinal/genetics , Pyrimidines/pharmacology , RNA Splicing/drug effects , Survival of Motor Neuron 2 Protein/genetics , Animals , Azo Compounds/adverse effects , Azo Compounds/therapeutic use , Humans , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , SafetyABSTRACT
The rational design of a novel series of pyrrolidine derivatives as neurokinin-3 receptor antagonists is reported starting from a selective neurokinin-1 receptor antagonist. Typical representatives in this series showed in vivo efficacy after oral administration in a NK3 mediated functional assay. This series of NK3 antagonists shows promise to deliver a novel antipsychotic.
Subject(s)
Pyrrolidines/pharmacology , Receptors, Neurokinin-3/antagonists & inhibitors , Administration, Oral , Drug Design , Models, Molecular , Pyrrolidines/administration & dosage , Pyrrolidines/chemistryABSTRACT
A series of tetrahydro-cyclopenta[b]indoles modulating the activity of the liver-X-receptor (LXR) were derived from a high throughput screening hit. The potency and selectivity for LXRbeta versus LXRalpha was improved. One compound, administered to wild-type mice modestly increased plasma HDL-cholesterol with no change in plasma triglycerides (TG) and reduced effects on liver TG content compared to T0901317. This novel series of LXR agonists shows promise to improve therapeutic efficacy with reduced potential to increase TG.
