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.
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Date of publication: 25 February 2020; Journal of Medicinal Chemistry
Author information: Xiaozheng Dou (1,2); Dinesh Nath (1,2); Henry Shin (3); Elmar Numemmedov (4); Philip C. Bourne (2); Jian-Xing Ma (3); & Adam S. Duerfeldt (1,2)
(3) Department of Physiology, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Boulevard, Oklahoma City, Oklahoma 73104, United States
(4) John Wayne Cancer Institute & Pacific Neuroscience Institute at Providence Saint John’s Health Center, 2200 Santa Monica Boulevard, Santa Monica, California 90404, United States