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

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

SUBMITTER: Dou XZ 

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

REPOSITORIES: biostudies-literature