Small molecule agonism of PPARα represents a promising new avenue for the development of non-invasive treatments for oculovascular diseases like diabetic retinopathy and age-related macular degeneration. Herein we report initial structure–activity relationships for the newly identified quinoline-based PPARα agonist, Y-0452. Preliminary computational studies led to the hypothesis that carboxylic acid transposition and deconstruction of the Y-0452 quinoline system would enhance ligand–protein interactions and better complement the nature of the binding pocket. A focused subset of analogs was designed, synthesized, and assessed for PPARα agonism. Two key observations arose from this work 1) contrary to other PPARα agonists, incorporation of the fibrate “head-group” decreases PPARα selectivity and instead provides pan-PPAR agonists and 2) computational models reveal a relatively unexploited amphiphilic pocket in PPARα that provides new opportunities for the development of novel agonists. As an example, compound 10 exhibits more potent PPARα agonism (EC50 = ∼6 µM) than Y-0452 (EC50 = ∼50 µM) and manifests >20-fold selectivity for PPARα over the PPARγ and PPARδ isoforms. More detailed biochemical analysis of 10 confirms typical downstream responses of PPARα agonism including PPARα upregulation, induction of target genes, and inhibition of cell migration.

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Date of publication: 5 April 2018; Bioorganic & Medicinal Chemistry Letters

Author information: Xiao-Zheng Dou (1); Dinesh Nath (1); Younghwa Shin (2); Jian-Xing Ma (2); & Adam S. Duerfeldt (1)

(1) Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, United States
(2) Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States