Visual Overview
Abstract
Modulators of the visual cycle have been developed for treatment of various retinal disorders. These agents were designed to inhibit retinoid isomerase [retinal pigment epithelium-specific 65 kDa protein (RPE65)], the rate-limiting enzyme of the visual cycle, based on the idea that attenuation of visual pigment regeneration could reduce formation of toxic retinal conjugates. Of these agents, certain ones that contain primary amine groups can also reversibly form retinaldehyde Schiff base adducts, which contributes to their retinal protective activity. Direct inhibition of RPE65 as a therapeutic strategy is complicated by adverse effects resulting from slowed chromophore regeneration, whereas effective retinal sequestration can require high drug doses with potential off-target effects. We hypothesized that the RPE65-emixustat crystal structure could help guide the design of retinaldehyde-sequestering agents with varying degrees of RPE65 inhibitory activity. We found that addition of an isopropyl group to the central phenyl ring of emixustat and related compounds resulted in agents effectively lacking in vitro retinoid isomerase inhibitory activity, whereas substitution of the terminal 6-membered ring with branched moieties capable of stronger RPE65 interaction potentiated inhibition. The isopropyl derivative series produced discernible visual cycle suppression in vivo, albeit much less potently than compounds with a high affinity for the RPE65 active site. These agents were distributed into the retina and formed Schiff base adducts with retinaldehyde. Except for one compound [3-amino-1-(3-isopropyl-5-((2,6,6-trimethylcyclohex-1-en-1-yl)methoxy)phenyl)propan-1-ol (MB-007)], these agents conferred protection against retinal phototoxicity, suggesting that both direct RPE65 inhibition and retinal sequestration are mechanisms of potential therapeutic relevance.
Footnotes
- Received February 11, 2017.
- Accepted May 1, 2017.
↵1 P.D.K., J.Z., and M.B. contributed equally to this work.
This research was supported in part by grants from the National Institutes of Health [Grants EY009339, EY027283, and EY024864 to K.P.; Grant CA157735 to G.P.T.; and Core Grants P30EY011373 and P30EY025585]; the Department of Veterans Affairs [Grant IK2BX002683 to P.D.K.; Research Career Scientist to N.S.P.); Research to Prevent Blindness; the National Science Foundation [Grant MRI-1334048] for NMR instrumentation; and the Arnold and Mabel Beckman Foundation. This work is based in part upon research conducted at the APS Northeastern Collaborative Access Team beamlines supported by the National Institutes of Health [Grants GM103403 and RR029205] and the Department of Energy [Grant DE-AC02-06CH11357]. K.P. is the John H. Hord Professor of Pharmacology.
K.P. is an inventor of U.S. Patent No. 8722669 (“Compounds and Methods of Treating Ocular Disorders”) and U.S. Patent No. 20080275134 (“Methods for Treatment of Retinal Degenerative Disease”) issued to Case Western Reserve University (CWRU), whose values may be affected by this publication. CWRU may license this technology for commercial development.
- U.S. Government work not protected by U.S. copyright
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