Pan Zhongshu, Zhang Jiaming, Zuo Haoyu, Li Cunrui, Song Huiying, Yang Haohan, Wu Keling, Zhao Minglei, Zhang Zirong, Lai Yuhua, Luo Jingyi, Wu Jianbing, Zhao Ling, Huang Zhangjian
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, P. R. China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, P. R. China.
J Med Chem. 2025 Apr 24;68(8):8600-8617. doi: 10.1021/acs.jmedchem.5c00269. Epub 2025 Apr 14.
Based on two major risk factors of glaucoma, elevated intraocular pressure (IOP) and senescence, two new series of nitric oxide (NO) donating dasatinib derivatives -, - were designed, synthesized, and biologically evaluated. The results demonstrated that the most active compound effectively released NO and increased the concentration of 3',5'-cyclic guanosine monophosphate in human trabecular meshwork cells, as well as maintained senolytic activity. Topical administration of in chronic ocular hypertension (COHT) glaucoma mice not only significantly eliminated senescent cells in retina but also exhibited potent retinal ganglion cells (RGCs) surviving, IOP lowering, and visual function protection activities, which were superior to those of dasatinib. Compared with younger adult mice, aged COHT mice resulted in more severe RGCs loss, while demonstrated a greater capacity to improve RGCs survival. Our findings show that dual IOP lowering and senolytic functions could be a promising therapeutic strategy for glaucoma, particularly in older patients.
基于青光眼的两个主要风险因素——眼压升高和衰老，设计、合成并对两个新系列的释放一氧化氮（NO）的达沙替尼衍生物进行了生物学评估。结果表明，活性最高的化合物能有效释放NO，并增加人小梁网细胞中3',5'-环磷酸鸟苷的浓度，同时保持衰老细胞溶解活性。在慢性高眼压（COHT）青光眼小鼠中局部应用该化合物，不仅能显著清除视网膜中的衰老细胞，还表现出强大的视网膜神经节细胞（RGC）存活、降低眼压和保护视觉功能的活性，优于达沙替尼。与年轻成年小鼠相比，老年COHT小鼠的RGC损失更严重，而该化合物在改善RGC存活方面表现出更大的能力。我们的研究结果表明，降低眼压和衰老细胞溶解的双重功能可能是一种有前景的青光眼治疗策略，特别是对于老年患者。
