BCOOL (Biological Chemistry, Organic and Organometallic Lecture) Series

The rapid and excessive buildup of cytotoxic lipofuscin bisretinoids is hypothesized to be the major contributor of the underlying pathophysiology of Stargardt disease. Furthermore, retinal bisretinoid accumulation may also play a critical role in the development and progression of atrophic age-related macular degeneration (AMD). These bisretinoids are a byproduct of the visual cycle, which is fueled by all-trans-retinol delivered to the retina via a tertiary retinol-binding protein 4 (RBP4)–transthyretin (TTR)–retinol complex. We will describe the discovery and development of tinlarebant, a selective RBP4 antagonist that dissociates circulating RBP4-TTR-retinol complexes, effectively reduces serum RBP4 levels in vivo, and inhibits bisretinoid synthesis in models of enhanced retinal lipofuscinogenesis. Tinlarebant is currently in Phase 3 clinical trials for Stargardt disease and atrophic AMD.