Design, Synthesis, and Structure-Activity Relationships of Biaryl Anilines as Subtype-Selective PPAR-alpha Agonists

Julia J. Lee, Ziwei Hu, Yuhong Anna Wang, Dinesh Nath, Wentao Liang, Yi Cui, Jian Xing Ma, Adam S. Duerfeldt

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The role of peroxisome proliferator-activated receptor alpha (PPARα) in retinal biology is clarifying, and evidence demonstrates that novel PPARα agonists hold promising therapeutic utility for diseases like diabetic retinopathy and age-related macular degeneration. Herein, we disclose the design and initial structure-activity relationships for a new biaryl aniline PPARα agonistic chemotype. Notably, this series exhibits subtype selectivity for PPARα over other isoforms, a phenomenon postulated to be due to the unique benzoic acid headgroup. This biphenyl aniline series is sensitive to B-ring functionalization but allows isosteric replacement, and provides an opportunity for C-ring extension. From this series, 3g, 6j, and 6d were identified as leads with <90 nM potency in a cell-based luciferase assay cell and exhibited efficacy in various disease-relevant cell contexts, thereby setting the stage for further characterization in more advanced in vitro and in vivo models.

Original languageEnglish (US)
Pages (from-to)766-776
Number of pages11
JournalACS Medicinal Chemistry Letters
Volume14
Issue number6
DOIs
StatePublished - Jun 8 2023

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society.

Keywords

  • Diabetic Retinopathy
  • PPARα
  • Retina
  • Structure−Activity Relationships

PubMed: MeSH publication types

  • Journal Article

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