SUMMARY Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness among working-age adults around the world. Currently, there is no non-invasive treatment demonstrated to fully blunt DR progression. Thus, a new drug for long-term prevention and treatment is urgently needed to improve the management for DR. Recently, two independent prospective clinical trials (FIELD and ACCORD) have identified that fenofibrate (a PPARα agonist) has unprecedented therapeutic effects in DR. Our previous experiment has confirmed PPARα down-regulation induced by diabetes plays a key pathogenic role in DR, further suggesting that PPARα is a promising drug target for DR. However, fenofibrates is a low potency PPARα agonist, which makes it not an ideal treatment option for DR and has not been approved as an anti-DR drug by FDA. Therefore, the development of novel oral drugs using PPARα agonists is an unmet clinical need. Recently, our team has independently designed, synthesized and screened more than 200 novel small molecule compounds, with different crystal structures from fenofibrate using PPARα 3D modeling. A190(EC50 = ∼27 nM) is selected as the leader compound since it possesses significant PPAR α agonist feature. A190 exhibited improved potency for PPARα agonism (~2700 fold higher than its parent compound Y-0452 EC50 = ∼50 µM and fenofibrate). Importantly, A190 has also proven to be potentially more effective than fenofibrate in the protection of retinal neurons and vascular cells in vitro. These findings suggest that A190 is a novel PPARα agonist with higher therapeutic potential for DR than fenofibrate. This project will serve as a proof-of-concept study to investigate the effects of the novel PPARα agonist A190 in a diabetic animal model. The program includes two specific aims. 1: Determine whether A190 reduces retinal inflammation and vascular leakage in a diabetic model. 2: Determine whether A190 protects retinal neurons in a diabetic model. This SBIR Phase I project will evaluate the effect of this novel PPARα agonist A190 on retinal oxidative stress, inflammation, neuron apoptosis and vascular leakage in a diabetic animal model, and lay a solid groundwork for future development of this drug candidate, such as pharmacokinetic (PK) and safety studies, in the Phase II preclinical studies.