Structure-guided evolution of a 2-phenyl-4-carboxyquinoline chemotype into PPARα selective agonists: New leads for oculovascular conditions

Xiao Zheng Dou, Dinesh Nath, Younghwa Shin, Jian Xing Ma, Adam S. Duerfeldt

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2717-2722
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number16
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

Bibliographical note

Funding Information:
Research reported in this publication was supported by the National Eye Institute of the National Institutes of Health under award number R21EY028279 (A.S.D.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
Research reported in this publication was supported by the National Eye Institute of the National Institutes of Health under award number R21EY028279 (A.S.D.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

  • Age-related macular degeneration
  • Diabetic retinopathy
  • PPAR selectivity
  • PPARα
  • Structure-based design

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