PDE4B Inhibitors for Treating Brain Injury

 描述(由申请人提供)：这项提案将开发一种新的小分子药物，用于脑外伤后慢性患者的临床试验，该患者在首次脑损伤后数月至数年仍有慢性认知障碍。根据疾病控制中心的数据，大约有300万美国人患有脑外伤后的认知障碍。这包括因运动受伤而遭受多发性脑震荡的人，部署后患有脑震荡综合征的武装部队人员，以及遭受意外伤害的人。这是一种未得到满足的医疗需求，也没有足够的治疗剂。我们的团队建议开发一种磷酸二酯酶-4B(PDE4B)抑制剂，作为治疗脑外伤后认知障碍的药物。这将是一种一流的药物，具有针对以前在人类临床试验中从未探索过的治疗靶点的新颖、创新的作用机制。 我们的初步数据表明，在脑损伤后3个月开始使用PDE4B抑制剂治疗大鼠，可以改善学习和记忆的多个领域。PDE4B亚型选择性抑制剂避免了早期PDE4抑制剂抑制所有PDE4亚型的众所周知的呕吐副作用。因此，PDE4B抑制剂是治疗脑外伤后慢性认知障碍的潜在突破性药物，具有更好的耐受性。这项第一阶段的STTR旨在解决目前PDE4B抑制剂(A-33)的局限性，因为它在大脑中的分布有限。利乐发现了一系列新的PDE4B抑制剂，显著改善了大脑分布。因此，该项目的目标是了解新的PDE4B抑制剂家族的样本(T-094)是否在具有足够的安全性和耐受性的脑损伤后模型中受益。这项建议有以下三个目标。目的1在大鼠颅脑损伤模型上评价T-094的疗效。将评估多个内存任务和内存域。通过/不通过的成功标准将是与使用车辆治疗的脑外伤动物相比，认知能力的改善。在目标2中，T-094将针对一组GPCR、离子通道、转运体和心脏HERG通道进行脱靶活性评估。通过/不通过的成功标准将是基于预期的脑暴露疗效的可接受的安全边际。在目标3中，将在雪貂呕吐模型中评估T-094的耐受性，以确定呕吐的无可观察效应水平(NOEL)。Go/No-Go标准将是治疗指数&gt；50倍，比较NOEL的血浆和脑暴露对雪貂的呕吐耐受性，以及改善脑损伤后大鼠认知的脑暴露。第二阶段项目将过渡到SBIR，用于在其他TBI模型中评估T-094，比较物种中的代谢物谱以进行毒理学评估，评估非啮齿动物物种的药代动力学，并完成在老鼠身上进行剂量范围发现毒理学研究。

 DESCRIPTION (provided by applicant): This proposal will develop a new, small molecule drug to be advanced into human clinical trials in the chronic post-TBI patient, who still has chronic cognitive impairments months to years after the initial TBI. According to the Centers for Disease Control, approximately 3 million Americans suffer from post-TBI cognitive impairments. This includes people sustaining multiple concussions due to sports injury, Armed Forces personnel post- deployment with post-concussive syndrome, and persons sustaining accidental injury. This is an unmet medical need for which there is no adequate therapeutic agent. Our team proposes to develop a phosphodiesterase-4B (PDE4B) inhibitor as a therapeutic for post-TBI cognitive impairment. This will be a first-in-class drug with a novel, innovative mechanism of action against a therapeutic target that has not been explored previously in human clinical trials. Our preliminary data demonstrate that treatment of brain-injured rats with a PDE4B inhibitor beginning 3 months after injury improves multiple domains of learning and memory. PDE4B subtype-selective inhibitors avoid the well-known emetic side-effect of earlier PDE4 inhibitors that inhibit all subtypes of PDE4. Thus, PDE4B inhibitors are potentially breakthrough drugs for treating chronic cognitive deficits after TBI with improved tolerability. This Phase I STTR seeks to address limitations of the current PDE4B inhibitor (A-33) which has limited distribution to brain. Tetra has discovered a new series of PDE4B inhibitors with significantly improved brain distribution. Therefore, the goal of the project is to learn if an exemplar of the new family of PDE4B inhibitors (T-094) has benefit in the post-TBI model with adequate safety and tolerability. This proposal has the following three Aims. Aim 1 will evaluate the efficacy of T-094 in a rat TBI model. Multiple memory tasks and domains of memory will be evaluated. Go/No-Go criteria for success will be improvement in cognitive performance in comparison to TBI animals treated with vehicle. In Aim 2, T-094 will be evaluated for off-target activity against a panel of GPCR, ion channels, transporters and the cardiac hERG channel. Go/No-Go criteria for success will be acceptable safety margin based on anticipated brain exposure for efficacy. In Aim 3, T-094 will be assessed for tolerability in the ferret emesis model to determine the no observable effect level (NOEL) for emesis. Go/No-Go criteria will be a Therapeutic Index of >50 fold comparing plasma and brain exposure at the NOEL for emetic tolerability in ferret versus plasma and brain exposure that improves cognition in post-TBI rats. The Phase II project will transition to an SBIR for the evaluation of T-094 in additional TBI models, compare metabolite profiles in species to conduct toxicological assessments, assess pharmacokinetics in non-rodent species, and to complete dose-range finding toxicological studies in rat.