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OptoDrum

Publication

April 25, 2025 • ✎ STRIA TECH

Identification of Nitric Oxide Donating Dasatinib Derivatives with Intraocular Pressure Lowering and Senolytic Activities

Topics:

Glaucoma

The Optic Nerve, its Neurons and Diseases

Publication

Journal of Medicinal Chemistry (Apr 24, 2025) Identification of Nitric Oxide Donating Dasatinib Derivatives with Intraocular Pressure Lowering and Senolytic Activities

Pan Z, Zhang J, Zuo H, Li C, Song H, Yang H, Wu K, Zhao M, Zhang Z, Lai Y, Luo J, Wu J, Zhao L, Huang Z

DOI: 10.1021/acs.jmedchem.5c00269 >>

Pan et al. investigated new compounds aimed at treating visual disorders such as glaucoma and aging. Using advanced medicinal chemistry techniques, they designed and tested these compounds for their ability to protect or restore vision in preclinical mouse models. To objectively measure the effects of these treatments on vision, Pan et al. employed the OptoDrum system, allowing the researchers to efficiently evaluate how well the new compounds preserved or improved visual function. This approach provided robust, reproducible data supporting the potential of these compounds as future therapies for eye diseases.

Based on two major risk factors of glaucoma, elevated intraocular pressure (IOP) and senescence, two new series of nitric oxide (NO) donating dasatinib derivatives 1a-f, 2a-f were designed, synthesized, and biologically evaluated. The results demonstrated that the most active compound 2e 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 2e 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 2e 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.