Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif
Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif
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DOI：
10.1021/acs.jmedchem.3c00461
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发表时间：
2023-06-06
影响因子：
7.3
通讯作者：
Tochtrop，Gregory P.
中科院分区：
文献类型：
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作者：
Bassetto，Marco;Zaluski，Jordan;Tochtrop，Gregory P.
在眼睛中，全反式-视黄醛异构化为11-顺式-视黄醛是通过称为视觉循环的代谢途径完成的，该代谢途径对视觉至关重要。RPE 65是该通路中必需的反式顺式异构酶。Emixustat是一种类维生素A模拟RPE 65抑制剂，被开发为治疗性视觉周期调节剂，用于治疗视网膜病变。然而，药代动力学缺陷限制了其进一步发展，包括：（1）γ-氨基-α-芳基醇的代谢脱氨基，其介导靶向RPE 65抑制，和（2）不需要的持久RPE 65抑制。我们试图通过更广泛地定义RPE 65识别基序的结构-活性关系来解决这些问题，该结构-活性关系是通过合成一系列新型衍生物来实现的，这些衍生物在体外和体内进行了RPE 65抑制测试。我们鉴定了一种有效的仲胺衍生物，其具有抗脱氨基作用并保留了RPE 65抑制活性。我们的数据提供了对emixustat分子的活性保留修饰的见解，这些修饰可用于调节其药理学性质。
In the eye, the isomerization of all-trans-retinal to 11-cis-retinal is accomplished by a metabolic pathway termed the visual cycle that is critical for vision. RPE65 is the essentialtrans–cisisomerase of this pathway. Emixustat, a retinoid-mimetic RPE65 inhibitor, was developed as a therapeutic visual cycle modulator and used for the treatment of retinopathies. However, pharmacokinetic liabilities limit its further development including: (1) metabolic deamination of the γ-amino-α-aryl alcohol, which mediates targeted RPE65 inhibition, and (2) unwanted long-lasting RPE65 inhibition. We sought to address these issues by more broadly defining the structure–activity relationships of the RPE65 recognition motif via the synthesis of a family of novel derivatives, which were testedin vitroandin vivofor RPE65 inhibition. We identified a potent secondary amine derivative with resistance to deamination and preserved RPE65 inhibitory activity. Our data provide insights into activity-preserving modifications of the emixustat molecule that can be employed to tune its pharmacological properties.