Age-related macular degeneration (AMD) is the most common cause of legal blindness in the US. There is no FDA-approved treatment for the most prevalent dry (atrophic) form of AMD. Dry AMD represents a slowly progressing neurodegenerative disorder in which specialized neurons (rod and cone photoreceptors) die in the central part of the retina called macula. Dry AMD is triggered by abnormalities in the retinal pigment epithelium (RPE) which induce secondary degeneration of photoreceptor cells. Excessive accumulation of lipofuscin granules in RPE is thought to cause degeneration of RPE and adjacent photoreceptors in AMD retinas. The major cytotoxic component of RPE lipofuscin is a pyridinium bisretinoid A2E which is formed as a by-product of a properly functioning visual cycle. It was suggested that visual cycle inhibitors may reduce the formation of A2E/lipofuscin and prolong RPE and photoreceptor survival In AMD. Rates of the visual cycle and A2E production depend on the influx of all-trans retinol from serum to the RPE. Formation of the tertiary retinol-binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex in serum is required for retinol uptake from circulation to the RPE. Without Interacting with TTR, the RBP4-retlnol complex is rapidly cleared from circulation due to glomerular filtration. Retinol-binding site on RBP4 is sterically proximal to the Interface mediating the RBP4-TTR interaction. Non-toxic compounds that compete with serum retinol for binding to RBP4 while blocking the RBP4-TTR interaction would reduce serum retinol, slow down the visual cycle, and inhibit formation of cytotoxic A2E. Two chemically distinct compounds known to be antagonists of RBP4-TTR interaction are proposed for medicinal chemistry optimization in the current study. The overall goal of the proposed project is to develop potent and selective RBP4 antagonists with pre-clinical efficacy, pharmacokinetic, and safety profiles supporting testing of optimized RBP4 antagonists in Phase I clinical trials. To achieve this goal, the studies outlined In this proposal will seek to conduct medicinal chemistry optimization of two compounds using a battery of primary, secondary and counter-screen assays for assessing compound potency and specificity (Specific Aim 1) and to assess preclinical efficacy of candidate compounds in appropriate animal models at different stages of compound optimization (Specific Aim 2).