Design, development and evaluation of novel dual PPARδ/PPARγ agonists

Symon Gathiaka, Gayani Nanayakkara, Tracey Boncher, Orlando Acevedo, Johnathon Wyble, Sagar Patel, Akash Patel, Mary Elizabeth Shane, Blake Bonkowski, Jason Wieczorek, Yinghui Rong, Kevin Huggins, Forest Smith, Rajesh H. Amin

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Type 2 diabetes is at epidemic proportions and thus development of novel pharmaceutical therapies for improving insulin sensitivity has become of paramount importance. The objectives of the current study were to develop novel dual PPARγ/δ agonists without the deleterious side effects associated with full PPARγ agonists. Docking simulations of 23 novel compounds within the ligand binding domain of PPARγ/δ were performed using AutoDock Vina which consistently reproduced experimental binding poses from known PPAR agonists. Comparisons were made and described with other docking programs AutoDock and Surflex-Dock (from SYBYL-X). Biological evaluation of compounds was accomplished by transcriptional promoter activity assays, quantitative PCR gene analysis for known PPARγ/δ targets as well as in vitro assays for lipid accumulation and mitochondrial biogenesis verses known PPAR agonists. We found one (compound 9) out of the 23 compounds evaluated, to be the most potent and selective dual PPARγ/δ agonist which did not display the deleterious side effects associated with full PPARγ agonists.

Original languageEnglish (US)
Pages (from-to)873-879
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number3
DOIs
StatePublished - Feb 1 2013
Externally publishedYes

Keywords

  • Adiposity
  • AutoDock vina
  • Diabetes
  • Peroxisomal proliferator activating receptor (PPAR)
  • Transciptional activity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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