Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPARα is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an streptozotocin-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogues, which led to the discovery of 4u and related compounds that reach cellular potencies <50 nM and exhibit >2,700-fold selectivity for PPARα over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.