Risdiplam (RG7916)
(Synonyms: RG7916; RO7034067) 目录号 : GC30845
Risdiplam (RG7916) 是一种小分子 SMN2 前体 mRNA 剪接修饰剂,可促进外显子 7 的包含和全长 SMN2 mRNA 的产生,从而补偿 SMN1 的损失 。
Cas No.:1825352-65-5
Sample solution is provided at 25 µL, 10mM.
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| Cell experiment [1]: | |
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Cell lines |
SMA type I fibroblasts; SMA type I motor neurons |
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Reaction Conditions |
0-1µM |
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Applications |
Risdiplam (RG7916) was active in vitro in SMA patient-derived fibroblasts and in motor neurons generated from induced pluripotent stem cells (iPSCs) derived from SMA type 1 patient fibroblasts, promoting the inclusion of exon 7, to generate full-length (FL) mRNA. |
| Animal experiment [1]: | |
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Animal models |
Adult C/C-allele miceand Neonatal Δ7 Mouse Model |
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Preparation Method |
Adult C/C-allele mice with mild SMA phenotype were treated for 10 days withRisdiplam (RG7916) given once a day orally at three different doses (1, 3, and 10 mg/kg). The level of SMN protein was assessed in brain and in quadriceps muscle. In the Δ7 mouse model of severe SMA, Risdiplam (RG7916) was administered by intraperitoneal (ip) injection once daily starting on postnatal day (PND) 3 and continued through PND9. The level of SMN protein was assessed in brain and in quadriceps muscle as well. |
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Dosage form |
Adult C/C-allele mice：1, 3, and 10 mg/kg;10 days;p.o. Δ7 mouse model：0-3mg/kg;6 days;i.p. |
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Applications |
Risdiplam (RG7916) potently increases SMN protein in both brain and muscle tissues of transgenic mouse models of SMA. |
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References: [1].Ratni H, Ebeling M,et,al. 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. PMID: 30044619. |
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Risdiplam (RG7916) is a small molecule SMN2 pre-mRNA splicing modifier that promotes the inclusion of exon 7 and production of full-length SMN2 mRNA, which can compensate for the loss of SMN1 [1-2].
Risdiplam (RG7916)(0-1μM) was active in vitro in SMA patient-derived fibroblasts and in motor neurons generated from induced pluripotent stem cells (iPSCs) derived from SMA type 1 patient fibroblasts, promoting the inclusion of exon 7, to generate full-length (FL) mRNA[1].
Risdiplam (RG7916) potently increases SMN protein in both brain and muscle tissues of transgenic mouse models of SMA[1]. In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam(0.08-0.2mg/kg/day)led to an increased expression of functional SMN protein in the blood[3].
References:
[1]. Ratni H, Ebeling M,et,al. 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. PMID: 30044619.
[2]. Singh RN, Ottesen EW, et,al. The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy. Neurosci Insights. 2020 Nov 23;15:2633105520973985. doi: 10.1177/2633105520973985. PMID: 33283185; PMCID: PMC7691903.
[3]. Baranello G, Darras BT, et,al. FIREFISH Working Group. Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med. 2021 Mar 11;384(10):915-923. doi: 10.1056/NEJMoa2009965. Epub 2021 Feb 24. PMID: 33626251.
Risdiplam (RG7916) 是一种小分子 SMN2 前体 mRNA 剪接修饰剂,可促进外显子 7 的包含和全长 SMN2 mRNA 的产生,从而补偿 SMN1 的损失 [1-2] 。
Risdiplam (RG7916)(0-1μM) 在 SMA 患者来源的成纤维细胞和源自 SMA 1 型患者成纤维细胞的诱导多能干细胞 (iPSC) 生成的运动神经元中具有体外活性,促进外显子 7 的包含,生成全长 (FL) mRNA[1]。
Risdiplam (RG7916) 有效增加 SMA 转基因小鼠模型大脑和肌肉组织中的 SMN 蛋白[1]。在患有1型脊髓性肌萎缩症的婴儿中,口服risdiplam(0.08-0.2mg/kg/day)治疗导致血液中功能性SMN蛋白的表达增加[3]。
| Cas No. | 1825352-65-5 | SDF | |
| 别名 | RG7916; RO7034067 | ||
| Canonical SMILES | O=C(C=C(C(C=C1C)=NN2C1=NC(C)=C2)N=C3C=C4)N3C=C4N(CCN5)CC65CC6 | ||
| 分子式 | C22H23N7O | 分子量 | 401.46 |
| 溶解度 | Ethanol : < 1 mg/mL (insoluble);DMSO : < 1 mg/mL (insoluble or slightly soluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4909 mL | 12.4545 mL | 24.9091 mL |
| 5 mM | 0.4982 mL | 2.4909 mL | 4.9818 mL |
| 10 mM | 0.2491 mL | 1.2455 mL | 2.4909 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs
Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene. A second gene, SMN2, produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1. Risdiplam (RG7916; RO7034067) is an orally administered, small-molecule SMN2 pre-mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n = 90), rats (n = 148), and monkeys (n = 24). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39 weeks. A parallel dose-dependent increase in SMN protein levels was seen in CNS and peripheral tissues in two SMA mouse models dosed with risdiplam. These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients' blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues.
Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)
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.
A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier
Aims: Risdiplam (RG7916, RO7034067) is an orally administered, centrally and peripherally distributed, survival of motor neuron 2 (SMN2) mRNA splicing modifier for the treatment of spinal muscular atrophy (SMA). The objectives of this entry-into-human study were to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of risdiplam, and the effect of the strong CYP3A inhibitor itraconazole on the PK of risdiplam in healthy male volunteers.
Methods: Part 1 had a randomized, double-blind, adaptive design with 25 subjects receiving single ascending oral doses of risdiplam (ranging from 0.6-18.0 mg, n = 18) or placebo (n = 7). A Bayesian framework was applied to estimate risdiplam's effect on SMN2 mRNA. The effect of multiple doses of itraconazole on the PK of risdiplam was also assessed using a two-period cross-over design (n = 8).
Results: Risdiplam in the fasted or fed state was well tolerated. Risdiplam exhibited linear PK over the dose range with a multi-phasic decline with a mean terminal half-life of 40-69 h. Food had no relevant effect, and itraconazole had only a minor effect on plasma PK indicating a low fraction of risdiplam metabolized by CYP3A. The highest tested dose of 18.0 mg risdiplam led to approximately 41% (95% confidence interval 27-55%) of the estimated maximum increase in SMN2 mRNA.
Conclusions: Risdiplam was well tolerated and proof of mechanism was demonstrated by the intended shift in SMN2 splicing towards full-length SMN2 mRNA. Based on these data, Phase 2/3 studies of risdiplam in patients with SMA are now ongoing.