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K. B. Phan, T. V. Bui, Y. Han, N. L. Mata; Development of Non-Retinoid Therapeutics for the Treatment of Lipofuscin-Based Retinopathies. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4534. doi: https://doi.org/.
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Excessive accumulation of lipofuscin and a toxic vitamin A-based fluorophore (A2E) has been implicated in the death of RPE and photoreceptor cells. Accumulation of these cellular toxins in the abca4 null mutant mouse can be completely halted by treatment with 4-hydroxyphenylretinamide (HPR). HPR competes with retinol for binding to serum retinol binding protein (RBP) leading to a reduction in serum RBP-retinol, visual cycle retinoids and, ultimately, A2E. HPR has had extensive human exposure and is generally well tolerated. However, teratogenic properties associated with HPR limit its usefulness in patients afflicted with juvenile-onset retinal diseases. To address this unmet need, we have sought to develop non-retinoid modulators (NRMs) which demonstrate the same mechanism of action as HPR and greater potency.
A proprietary high-throughput screen was used to identify small molecules which bind to RBP with high-affinity (< 1µM). Structure-activity relationships among these small molecules were compared in order to identify bioactive pharmacophores. Based on this comparison, new chemical entities (NCEs) were synthesized and submitted for screening. NCEs which demonstrated efficacy in vitro and minimal cytochrome P450 inhibition were administered to abcr null mutant mice to assess efficacy in vivo.
Biochemical characterizations showed that the synthesized NRMs possess increased water solubility and enhanced RBP-binding affinity compared to HPR. The NRMs also showed very little inhibition of key drug-metabolizing enzymes of the liver. Importantly, administration of the NRMs to abca4 null mutant mice produced dose-dependent reductions of RBP-retinol in serum and A2E in the RPE.
Findings of the present study validate modulation of serum RBP-retinol as a therapeutic modality for reducing the accumulation of lipofuscin and A2E in the eye. Enhanced water solubility, greater RBP-binding affinity and minimal liver enzyme toxicity of the synthesized NRMs make these compounds appropriate alternatives to HPR. Finally, physicochemical properties of the NRMs suggest that they will be amendable to formulation as orally available therapeutics.
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