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

ABSTRACT: Small molecule agonism of PPAR? 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 PPAR? 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 PPAR? agonism. Two key observations arose from this work 1) contrary to other PPAR? agonists, incorporation of the fibrate "head-group" decreases PPAR? selectivity and instead provides pan-PPAR agonists and 2) computational models reveal a relatively unexploited amphiphilic pocket in PPAR? that provides new opportunities for the development of novel agonists. As an example, compound 10 exhibits more potent PPAR? agonism (EC50?=??6?µM) than Y-0452 (EC50?=??50?µM) and manifests >20-fold selectivity for PPAR? over the PPAR? and PPAR? isoforms. More detailed biochemical analysis of 10 confirms typical downstream responses of PPAR? agonism including PPAR? upregulation, induction of target genes, and inhibition of cell migration.

SUBMITTER: Dou XZ 

PROVIDER: S-EPMC6119630 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature