{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Bassetto M"],"funding":["BLRD VA","NEI NIH HHS","National Eye Institute","Research to Prevent Blindness","Knights Templar Eye Foundation","Retina Research Foundation","U.S. Department of Veterans Affairs","NIGMS NIH HHS"],"pagination":["17638-17652"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12409883"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["68(16)"],"pubmed_abstract":["The visual cycle is a metabolic pathway essential for visual function. The bisretinoid byproducts of this pathway can induce retinal toxicity, as occurs in Stargardt disease type 1 (STGD1). Emixustat, which inhibits bisretinoid production, is a visual cycle modulator (VCM) that targets RPE65. However, it causes visual impairment due to its unfavorable duration of action. Here, we report ester-containing analogs of emixustat that are susceptible to hydrolytic clearance and function as short-acting VCMs. We show that the esterase-mediated metabolism of these compounds can be tuned while maintaining high-affinity RPE65 targeting. Compounds <b>6</b> (EYE-002) and <b>7</b> (EYE-003) containing diethyl acetate and valproate esters, respectively, allowed faster recovery of visual cycle function compared to emixustat. These molecules protected against retinal degeneration in mouse models of photic retinopathy and STGD1. These data demonstrate that shorter attenuation of the visual cycle can therapeutically intervene in retinal diseases with fewer visual side effects compared to emixustat."],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Rationally Designed, Short-Acting RPE65 Inhibitors for Visual Cycle-Associated Retinopathies."],"pmcid":["PMC12409883"],"funding_grant_id":["P30EY034070","P41 GM103393","R01EY009339","IK6 BX006800","R01 EY009339","I01 BX004939","I02BX004939","IK6BX006800","P30 EY034070"],"pubmed_authors":["Saraswat V","Palczewski K","Hu Y","Tochtrop GP","Bassetto M","Smidak R","Kiser PD","Li B","Chen X","Damacio F"],"additional_accession":[]},"is_claimable":false,"name":"Rationally Designed, Short-Acting RPE65 Inhibitors for Visual Cycle-Associated Retinopathies.","description":"The visual cycle is a metabolic pathway essential for visual function. The bisretinoid byproducts of this pathway can induce retinal toxicity, as occurs in Stargardt disease type 1 (STGD1). Emixustat, which inhibits bisretinoid production, is a visual cycle modulator (VCM) that targets RPE65. However, it causes visual impairment due to its unfavorable duration of action. Here, we report ester-containing analogs of emixustat that are susceptible to hydrolytic clearance and function as short-acting VCMs. We show that the esterase-mediated metabolism of these compounds can be tuned while maintaining high-affinity RPE65 targeting. Compounds <b>6</b> (EYE-002) and <b>7</b> (EYE-003) containing diethyl acetate and valproate esters, respectively, allowed faster recovery of visual cycle function compared to emixustat. These molecules protected against retinal degeneration in mouse models of photic retinopathy and STGD1. These data demonstrate that shorter attenuation of the visual cycle can therapeutically intervene in retinal diseases with fewer visual side effects compared to emixustat.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Aug","modification":"2026-05-29T21:43:12.178Z","creation":"2026-04-08T06:06:01.47Z"},"accession":"S-EPMC12409883","cross_references":{"pubmed":["40764714"],"doi":["10.1021/acs.jmedchem.5c01353"]}}