Small-molecule therapeutics for diabetic retinopathy: from VEGFR inhibitors to emerging non-VEGF targets

Diabetic retinopathy (DR) remains a leading cause of vision loss worldwide and is driven largely by chronic microvascular dysfunction dominated by vascular endothelial growth factor (VEGF) signaling. Although biologics have transformed anti-VEGF therapy, small molecules continue to attract interest because of their structural tunability, multitarget potential, and compatibility with diverse delivery platforms. In this review, we summarize the medicinal-chemistry progress of small-molecule therapeutics for DR, with emphasis not only on target classes and scaffold design, but also on the developmental advancement of representative agents. VEGF/VEGFR-directed programs now span early proof-of-concept inhibitors, ocularly optimized topical candidates, and clinically advanced depot-enabled tyrosine kinase inhibitors, whereas non-VEGF approaches include validated lead series targeting soluble epoxide hydrolase, STAT3, adiponectin receptors, integrins, and other mechanistically complementary pathways. Importantly, the field remains highly uneven: a limited number of compounds have achieved meaningful translational or clinical progress, while many others remain exploratory despite compelling biology. Taken together, current evidence suggests that the most promising future direction lies not in potency optimization alone, but in integrating scaffold design with ocular pharmacokinetics, formulation, and route-specific delivery to define realistic therapeutic niches in diabetic retinal diseases.