生物活性

• 描述Risdiplam is an optimized and brain penetrant SMN2 splicing modifier with EC_1.5× values of 4nM and 29nM for SMN2 splicing and SMN protein, as well as EC50 value of 67nM for FOXM1 splicing. Risdiplam is mainly used as a candidate drug for treatment of SMA (pinal muscular atrophy). Risdiplam was active in vitro in SMA patient-derived fibroblasts at concentration<1μM as it could dose-dependently increase the level of SMN2 mRNA and SMN protein. The increase of SMN protein in motor neurons generated from iPSCs derived from SMA type 1 patient fibroblasts could also be observed post Risdiplam treatment. Oral administration of Risdiplam at dose of 1, 3, and 10mg/kg once daily for 10 days could dose-dependently prolong the survival of adult C/C-allele mice with mild SMA phenotype. Potent increase of SMN protein could be observed in both brain and muscle tissues of transgenic mouse models of SMA. Intraperitoneal injection with Risdiplam at 0.1, 0.3, and 1mg/kg once daily for 12 days could rescue the loss of number of vGlut1 inputs, the number of motor neurons the percentage of fully innervated NMJs in the Δ7 mouse model of severe SMA, as well as increased muscle size in the extensor digitorum longus muscles compared with vehicle-treated group.

• 动物研究
  剂量	Mice: 1 mg/kg - 10 mg/kg[1] (p.o.) Cynomolgus monkey: 0.1 mg/kg, 1.9 mg/kg[1] (i.v.); 0.5 mg/kg, 5.5 mg/kg[1] (p.o.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Mice[1] Monkeys[1] Dose 1.9 mg/kg (i.v.) 5.5 mg/kg (p.o.) 0.1 mg/kg (i.v.) 0.5 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. F 100% (p.o.) 43% (p.o.) T1/2 6.4 h (p.o.) 5.4 h (p.o.) CL 8.9 ml/min/kg (i.v.) 5.7 ml/min/kg (i.v.) Vss 3.1 l/kg (i.v.) 2.0 l/kg (i.v.)