Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif

In the eye, the isomerization of all-trans-retinalto 11-cis-retinal is accomplished by a metabolicpathway termed the visual cycle that is critical for vision. RPE65is the essential trans-cis isomerase of this pathway. Emixustat, a retinoid-mimetic RPE65 inhibitor,was developed as a therapeutic visual cycle modulator and used forthe treatment of retinopathies. However, pharmacokinetic liabilitieslimit its further development including: (1) metabolic deaminationof the gamma-amino-alpha-aryl alcohol, which mediates targetedRPE65 inhibition, and (2) unwanted long-lasting RPE65 inhibition.We sought to address these issues by more broadly defining the structure-activityrelationships of the RPE65 recognition motif via the synthesis ofa family of novel derivatives, which were tested in vitro and in vivo for RPE65 inhibition. We identifieda potent secondary amine derivative with resistance to deaminationand preserved RPE65 inhibitory activity. Our data provide insightsinto activity-preserving modifications of the emixustat molecule thatcan be employed to tune its pharmacological properties.