{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:02:13Z","timestamp":1790265733380,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,21]]},"group-title":"Pharmacology and Toxicology","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Gund-Harrington National Initiative","award":["TA-NMT-1115-0690-COLU-GH"],"award-info":[{"award-number":["TA-NMT-1115-0690-COLU-GH"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Stargardt disease is a juvenile-onset retinal dystrophy characterized by the buildup of cytotoxic lipofuscin deposits in the retinal pigment epithelium (RPE), leading to photoreceptor degeneration and eventual blindness. Currently, there are no FDA-approved treatments for Stargardt disease. Bisretinoids, byproducts of the visual cycle, are the major cytotoxic components of the lipofuscin deposits, and bisretinoid synthesis relies on the traffic of retinol from the bloodstream to the retina. Selective targeting of the key retinol transporter, Retinol-Binding Protein 4 (RBP4), offers an appealing strategy for halting the buildup of lipofuscin in the RPE and arresting the progression of Stargardt disease. Retinol delivery depends on RBP4 interaction with another serum protein, Transthyretin (TTR). We previously reported several libraries of RBP4 antagonists that effectively blocked the association of the TTR-RBP4-retinol tertiary complex, thereby lowering the overall retinol load in the retina; however, some chemotypes displayed off-target activity that warranted further optimization. Here, we report the pharmacological characterization of AKR-XI-85 and its analogs as promising non-retinoid small-molecule RBP4 antagonists. AKR-XI-85 displayed excellent\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  efficacy and desirable pharmacokinetic properties without any limiting off-target activity. In\n                  <jats:italic>\n                    Abca4\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  mice, chronic dosing of the compound induced a prolonged reduction in serum RBP4 levels and achieved a dramatic, 70 % reduction in the accumulation of A2E, a critical component of toxic lipofuscin. As such, AKR-XI-85 may be an attractive drug candidate for the treatment of Stargardt disease and other lipofuscin-dependent retinopathies.\n                <\/jats:p>","DOI":"10.64898\/2026.09.14.751502","type":"posted-content","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T15:10:18Z","timestamp":1790003418000},"source":"Crossref","is-referenced-by-count":0,"title":["A non-retinoid triazolopyrimidine RBP4 antagonist for the treatment of Stargardt disease"],"prefix":"10.64898","author":[{"given":"K. 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