Aberrant activation of N-methyl-d-aspartate receptors (NMDAR) and the resulting neuronal nitric oxide synthase (nNOS) excessive activation play crucial pathogenic roles in neuronal damage caused by stroke. Disrupting postsynaptic density protein 95 (PSD95)-nNOS protein-protein interaction (PPI) has been proposed as a potential therapeutic strategy for ischemic stroke without incurring the unwanted side effects of direct NMDAR antagonism. Based on a specific PSD95-nNOS PPI inhibitor (SCR4026), we conducted a detailed study on structure-activity relationship (SAR) to discover a series of novel benzyloxy benzamide derivatives. Here, our efforts resulted in the best 29 (LY836) with improved neuroprotective activities in primary cortical neurons from glutamate-induced damage and drug-like properties. Whereafter, co-immunoprecipitation experiment demonstrated that 29 significantly blocked PSD95-nNOS association in cultured cortical neurons. Furthermore, 29 displayed good pharmacokinetic properties (T_1/2 = 4.26 and 4.08 h after oral and intravenous administration, respectively) and exhibited powerful therapeutic effects in rats subjected to middle cerebral artery occlusion (MCAO) by reducing infarct size and neurological deficit score. These findings suggested that compound 29 may be a promising neuroprotection agent for the treatment of ischemic stroke.

N-甲基-d-天冬氨酸受体（NMDAR）的异常激活和由此产生的神经元一氧化氮合酶（nNOS）的过度激活在中风引起的神经元损伤中发挥着至关重要的致病作用。破坏突触后密度蛋白 95 (PSD95)-nNOS 蛋白-蛋白相互作用 (PPI) 已被提议作为缺血性中风的潜在治疗策略，而不会产生直接 NMDAR 拮抗作用的不良副作用。基于特定的PSD95-nNOS PPI抑制剂（SCR4026 ），我们进行了详细的构效关系（SAR）研究，发现了一系列新型苄氧基苯甲酰胺衍生物。在这里，我们的努力产生了最好的29 ( LY836 )，其改善了初级皮质神经元的神经保护活性，使其免受谷氨酸诱导的损伤和药物样特性。此后，免疫共沉淀实验证明29显着阻断培养的皮层神经元中的 PSD95-nNOS 关联。此外，29 种药物表现出良好的药代动力学特性（口服和静脉给药后 T _1/2 分别为 4.26 和 4.08 小时），并通过减少梗塞面积和神经功能缺损评分，对大脑中动脉闭塞 (MCAO) 大鼠表现出强大的治疗作用。这些发现表明化合物29可能是治疗缺血性中风的有前途的神经保护剂。