腺苷受体A2A拮抗剂作为治疗帕金森综合症新型药物的可行性研究

Parkinson's disease (PD) is a neurodegenerative disease that affects 1-2% of people over the age of 65. The total economic burden of PD in the US was projected to be $23 billion annually. Clinical features of PD include bradykinesia, rigidity and tremor. As the disease progresses, other symptoms such as sleep abnormality, depression and cognitive decline emerge. The current drug therapies work relatively well for the motor symptoms, however, does little for the non-motor symptoms. There is a great urgency to discover and develop new drugs to address the motor and the non-motor symptoms for Parkinson's disease. Adenosine receptor antagonist emerged as a promising new class of compounds for the improved treatment of PD. Based on the receptor's locations and functions in the brain, the antagonists should be able to address the motor and the non-motor symptoms of PD, with minimum adverse central nerve system effects. Currently there are at least four compounds in clinical development. The applicant has been working in the field for many years and had developed adenosine receptor antagonist to the pre-clinical stage. The current research plan is to improve the structure features of the pre-clinical candidates to solve the active metabolite (improve drug developability), reactive metabolite (reduce drug toxicity) and chemical instability problems. Through the structure optimization we will create molecular entities different enough to obtain intellectual properties. We are hopeful that our work will contribute significantly for the new drug development based on novel target to treat Parkinson's disease.

帕金森综合症（Parkinson's Disease，PD）是一种慢性中枢神经退化的疾病，美国每年因PD带来的损失约为230亿美元。目前治疗PD的药物对病人的运动失调疗效较好，但对病人的情绪，睡眠与认知等方面疗效甚微，急需新药来提高病患者的生活质量。腺嘌呤核苷A2A受体拮抗剂不仅对运动失调有疗效，更有望缓解病人的情绪和认知症状。我们的前期工作成功开发出临床前候选化合物。本课题我们将以临床前候选化合物为基础，通过系统的构效优化解决活性中间体，活勃中间体与化学稳定性等问题，同时获取具有自主知识产权的候选化合物，并在PD的各种动物模型中检测化合物对运动和认知的疗效，为最终开发出全新靶点的治疗PD的药物奠定坚实基础。

腺苷受体A2A拮抗剂具有抗帕金森综合症的应用。本课题组先前基于乙酰氨基嘧啶骨架的腺苷受体拮抗剂各项指标良好，但是存在酰基容易水解的问题。将乙酰基换成杂环基和三氟乙基等生物等排体，得到了具有良好化学稳定性的化合物，但是在体外肝酶抑制测试中发现有潜在的安全性问题。我们对杂环氨基嘧啶骨架的腺苷受体拮抗剂进行结构优化，通过去除吡唑环上的两个甲基，降低其亲脂性（clogP），从而降低其对肝酶的抑制作用，解决了潜在的安全性问题。通过对所合成化合物的构效关系研究，我们筛选出活性较好的化合物进行后续的肝酶抑制活性测试、代谢稳定性测试、氟哌啶醇诱导的大鼠僵直动物模型测试，并对药物在血脑中的分布也进行了测定。实验结果表明，代表化合物对腺苷受体A2A的抑制活性良好，对CYP的抑制活性较弱，血脑屏障透过性良好，而且在氟哌啶醇诱导的大鼠僵直模型中看到了明显的效果，表明我们的化合物确实是体内有效的腺苷A2A受体拮抗剂。然而在后期的研究中发现以这类骨架为基础的化合物口服生物利用度较差。虽然展开进一步的结构优化，包括阻断代谢活性位点，提高分子整体亲水性等进一步的结构优化，却没有取得预期效果，没有能够筛选出较理想的先导化合物。我们在经过晶体结构对接的研究后，决定重新评估核心骨架结构。我们选定了全新氰基胺基嘧啶骨架为起点。进一步的构效关系研究表明，这类骨架不仅提供了活性优异的化合物，并且大幅提高了口服生物利用度。代表化合物对肝酶（CYP3A4， 2D6， 2C19等）无明显抑制作用，在哌啶酮引起的运动不能症的大鼠模型中显示了很好的药效，最终筛选出了先导化合物。依托本项目资助，课题组共发表一标SCI论文11篇，申请专利4项（其中授权1项）。项目于2016年初最终完成向工业界的转化