基于代谢型谷氨酸受体负变构调节剂的发现及其抗抑郁活性研究

Major depressive disorder is among the most prevalent forms of mental illness, becomes the world’s fourth largest disease. All currently mainly available antidepressant medications are 5-HT and/or norepinephrine selective reuptake inhibitors, but are characterized by a slow onset of action (frequently at least 3-4 weeks are required for manifestation of significant therapeutic effects), poor efficacy, and approximately 30% of patients are resistant to a series of treatment. To overcome these drawbacks, discovering novel mechanisms of pathophysiology of depression as well as more effective treatments are necessary. Recently, glutamate receptor has aroused widely public concern, several mGluR5 negative allosteric modulators enter into clinical studies for the treatment of depressive, such RG7090 from Roche. In our previous studies, we have designed and synthesized a series of novel compounds against mGluR5 on the basis of these clinical drugs via scaffold-hopping strategy. Compound ZD043 not only exhibits good biological potency in vitro and in vivo, but also give good bioavailability and BBB permeability. Therefore, in this project, we will launch a full SAR study for the lead compound ZD043, and obtain some more better biological activities lead compounds via further biological assay, pharmocokinetic study and safety evaluation

抑郁症是一种危害人类身心健康的情感障碍疾病，已经成为全球第四大疾病。当前临床上主要是以5-羟色胺或去甲肾上腺素再摄取抑制剂为主的第三代抗抑郁药物，尽管其副作用较第一代和第二代抗抑郁药物已大幅降低，但是存在起效慢、缓解率低和易复发等缺陷。因此，基于新机制去开发更加安全有效的抗抑郁药物已迫在眉睫。近年来，谷氨酸受体引起人们广泛的关注，其变构调节剂为抑郁症的治疗提供了新的希望，如RG7090等来自跨国药企的多个化合物进入了临床研究，展现出良好的成药性。我们在前期的研究中，也快速跟进(Fast Follow)这些临床化合物，合成了一系列新颖的结构，发现化合物ZD043具有良好的体内外药效、药代性质和脑靶向性(专利申请号: 201510179677.0)。因此，在本项目中，我们拟对先导化合物ZD043 进行系统的 SAR 研究、药代动力学和安全性评价，以期发现更优的先导化合物用于临床前研究。

抑郁症是一种危害人类身心健康的情感障碍疾病，已经成为全球第四大疾病。当前临床上主要是以5-羟色胺或去甲肾上腺素再摄取抑制剂为主的第三代抗抑郁药物，尽管其副作用较第一代和第二代抗抑郁药物已大幅降低，但是存在起效慢、缓解率低和易复发等缺陷。因此，基于新机制去开发更加安全有效的抗抑郁药物已迫在眉睫。在本研究中，我们基于抑郁症调控的新型靶点代谢性谷氨酸受体mGluR5开展了其变构调节剂的发现研究，并取得了一系列重要进展，发现了30余个活性与先导化合物相当或更优的目标化合物，化合物ZD043被选为候选药物进行全面的临床前研究，目前已经完成各项评价，预计2021年中可提交临床试验申请。通过本项目的基础研究，为后续抗抑郁新型药物候选化合物的发现奠定了坚实基础，项目执行期间获得中国、美国、日等国专利授权，共发表受资助文章10篇。

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