Design and Assessment of First-Generation Heterobifunctional PPARα/STING Modulators.

ABSTRACT: Inflammatory retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD) are prominent causes of blindness in industrialized countries. The complexity of these diseases, involving diverse cell types and pathways that give rise to a multifactorial pathogenesis, complicates drug discovery. As such, therapies exhibiting polypharmacology are expected to improve outcomes through broader disease stage coverage and beneficial spatiotemporal effects. We report herein the first dual modulator of PPARα and STING, two targets tied to disparate pathologies in retinal diseases. Recognizing structural similarities between a reported STING inhibitor SN-013 and our previously described PPARα agonist A229, we designed BH400, which agonizes PPARα (EC₅₀ = 1.2 μM)

SUBMITTER: Hu B 

PROVIDER: S-EPMC11318021 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature