Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders

Xiaozheng Dou, Dinesh Nath, Henry Shin, Elmar Nurmemmedov, Philip C. Bourne, Jian Xing Ma, Adam S. Duerfeldt

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)2854-2876
Number of pages23
JournalJournal of medicinal chemistry
Issue number6
StatePublished - Mar 26 2020
Externally publishedYes

Bibliographical note

Funding Information:
Research reported in this publication was supported by the University of Oklahoma Growth Fund (A.S.D., H.S., J.-X.M.) and the National Eye Institute of the National Institutes of Health under award numbers R21EY028279 (A.S.D.), R01EY019309, R01EY018659, and R01EY012231 (J.-X.M.). We acknowledge the use of the Protein Production Core (PPC) at the University of Oklahoma, Norman. PPC is supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103640. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors are grateful to Cameron D. Siler and Will Drover for enlightening discussions and Eurofins for conducting the PK studies.

Publisher Copyright:
Copyright © 2020 American Chemical Society.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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