选择性GlyT1抑制剂的设计、合成及抗精神分裂活性研究

Schizophrenia is a severe and chronic mental illness. The leading treatments for this central nervous system disorder are efficacious in the management of positive symptoms; however, they demonstrate minimal effects on negative symptoms and cognitive function. Preclinical and clinical evidence has accumulated suggesting that GlyT1 inhibitors can improve positive, negative, and cognitive symptoms in schizophrenic patients. Our groups have discovered several novel and potent GlyT1 inhibitors which show efficacy in phencyclidine-induced mouse model of schizophrenia, while their metabolic stability and CNS penetration still need to be improved. The patent of these compounds has been applied currently. Subsequent optimizations will be carried out to improve the drug-like properties of our GlyT1 inhibitors while retaining high GlyT1 potency. The primary objective is to improve their metabolic stability and increase brain penetration. Through several loop of druggability evaluation, we hope to get 1-2 new GlyT1 inhibitors with better metabolic stability and CNS penetration.

精神分裂症是一种严重的精神疾病。传统抗精神分裂药物对精神分裂症阳性症状有良好疗效，但对阴性症状和认知功能障碍效果不佳。研究表明甘氨酸转运体1(GlyT1)抑制剂有望克服现有药物的不足，成为对阳性症状、阴性症状和认知功能障碍都有效的抗精神分裂症药物。本研究前期设计并合成一系列结构新颖的GlyT1抑制剂，具有良好的体外和体内活性，该研究已经申请了专利保护。但其代谢稳定性和血脑屏障通透性有待提高。本课题拟通过结构优化和构代关系研究，提高化合物的代谢稳定性，优化其血脑屏障通透性，提高脑组织的药物浓度。拟通过本课题的实施，发现1-2个体内外药理效果明确、代谢稳定、通透性良好的GlyT1抑制剂，为进一步开发抗精神分裂的新药奠定基础。

精神分裂症是一种严重的精神疾病。传统抗精神分裂药物对精神分裂症阳性症状有良好疗效，但对阴性症状和认知功能障碍效果不佳。研究表明甘氨酸转运体1(GlyT1)抑制剂有望克服现有药物的不足，成为对阳性症状、阴性症状和认知功能障碍都有效的抗精神分裂症药物。在本课题组前期工作的基础上，在本基金的支持下，我们对前期发现的先导化合物展开全面的构效关系研究，明确了主要位点的构效关系，找到数十个活性在nM级的先导化合物；对体外高活性化合物反复进行结构优化和筛选，通过GlyT1/GlyT2选择性实验、体内药物代谢实验、血脑屏障通透性实验，最终候选化合物体内药物代谢性质优良，多种动物体内行为学实验优于阳性化合物或者与阳性化合物相当，后续开发正在进行中。本课题按计划进行，圆满完成了预期目标。