An Orally Bioavailable Drug Candidate for Spinal Muscular Atrophy

 描述（由申请人提供）：脊髓性肌萎缩症是一种由SMN 1基因突变引起的遗传性疾病，可导致运动神经元功能受损并可能导致死亡。目前还没有批准的药物用于这种使人衰弱的儿科疾病。我们的目标是产生一种用于治疗SMA的口服生物可利用药物，其上调SMN 2基因表达以补偿野生型SMN 1基因的缺失。这些药物可能与目前正在临床开发中的剪接调节剂或神经保护剂（如果获得批准）联合使用，以增加患者获益。在初步工作中，我们已经确定了一种具有优异体外活性和良好药代动力学的先导化合物，该化合物在SMN 107新生小鼠模型中上调SMN水平，而没有明显的不良反应。将设计、合成新的类似物，并评估其体外活性、细胞毒性以及体外ADME和安全性。将选择具有改善的细胞活性（全长SMN水平）、低细胞毒性和有利的体外安全性特征的类似物用于PK研究， 成年和新生小鼠。还将在大鼠PK模型（经口给药，不同时间点的血浆和脑水平）中研究这些类似物，以评估其在不同物种中的药代动力学。在耐受剂量下表现出有利脑PK特征（在新生小鼠中无明显不良反应）的类似物将在SMNΔ7新生小鼠中进行药效学（脑组织中的全长SMN水平）和疗效研究。同时，将使用亲和探针鉴定所选有效化合物的生物靶标，并研究SMN水平上调的机制。最后，一旦选择了临床前候选药物，（a）将优化给药方案，包括有效剂量范围确定和给药频率;（B）将进行一组全面的体外理化、ADME和安全性分析研究（详见表2，见下文）;和（c）将在大鼠和犬药代动力学和毒理学研究中评估PCC。在完成拟议研究后，我们将能够启动选定PCC的IND使能研究，并与适当的商业合作伙伴一起将该项目推进到临床研究。

 DESCRIPTION (provided by applicant): Spinal muscular atrophy is a genetic disease resulting from mutations in the SMN1 gene that results in impaired motor neuron function and can lead to death. Currently there are no approved drugs for this debilitating pediatric disease. Our goal is to generate an orally bioavailable drug for the treatment of SMA that upregulates SMN2 gene expression to compensate for the loss of the wild type SMN1 gene. Such drugs can likely be used in combination with the splicing modulators or neuroprotective agents (if approved) that are currently in clinical development to provide increased patient benefit. In preliminary work we have identified a lead compound with excellent in vitro activity and good pharmacokinetics that upregulates SMN levels in the SMN∆7 neonatal mouse model without obvious adverse effects. New analogs will be designed, synthesized and assessed for in vitro activity, cytotoxicity and in vitro ADME and safety profiles. Analogues with improved cellular activity (full-length SMN levels), low cytotoxicity and favorable in vitro safety profiles will be selected for PK studies in adult and neonatal mice. These analogs will also be studied in rat PK models (oral administration, plasma and brain levels at different time points) to assess their pharmacokinetics across different species. Analogs that exhibit favorable brain PK profiles at tolerated doses (without obvious adverse effects in neonatal mice) will be progressed to pharmacodynamic (full-length SMN levels in brain tissue) and efficacy studies in SMNΔ7 neonatal mice. In parallel the biological target of select potent compounds will be identified using affinity probes and the mechanism by which SMN levels are upregulated will be investigated. Finally, once a preclinical candidate is selected (a) the dosing regimen will be optimized including efficacious dose range determination and dosing frequency; (b) a comprehensive set of in vitro physicochemical, ADME and safety profiling studies (detailed in Table 2, vide infra) will be carried out; and (c) th PCC will be assessed in rat and dog pharmacokinetic and toxicology studies. Upon the completion of the proposed studies, we will be positioned to initiate IND-enabling studies for the selected PCC, and move the program forward into clinical studies with an appropriate commercial partner.