Discovery of Bispecific Antagonists of Retinol Binding Protein 4 That Stabilize Transthyretin Tetramers: Scaffolding Hopping, Optimization, and Preclinical Pharmacological Evaluation as a Potential Therapy for Two Common Age-Related Comorbidities

Accumulation
of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular
degeneration (AMD) pathogenesis. Retinal bisretinoid synthesis depends
on the influx of serum all-trans-retinol (1) delivered via a tertiary retinol binding protein 4 (RBP4)–transthyretin
(TTR)–retinol complex. We previously identified selective RBP4
antagonists that dissociate circulating RBP4–TTR–retinol
complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis
in models of enhanced retinal lipofuscinogenesis. However, the release
of TTR by selective RBP4 antagonists may be associated with TTR tetramer
destabilization and, potentially, TTR amyloid formation. We describe
herein the identification of bispecific RBP4 antagonist–TTR
tetramer kinetic stabilizers. Standout analogue (±)-44 possesses suitable potency for both targets, significantly lowers
mouse plasma RBP4 levels, and prevents TTR aggregation in a gel-based
assay. This new class of bispecific compounds may be especially important
as a therapy for dry AMD patients who have another common age-related
comorbidity, senile systemic amyloidosis, a nongenetic disease associated
with wild-type TTR misfolding.

细胞毒性脂褐素双视黄醇的积累可能对萎缩性年龄相关性黄斑变性（AMD）的发病机制产生贡献。视网膜双视黄醇的合成依赖于通过三级视黄醇结合蛋白4（RBP4）-转甲状腺素蛋白（TTR）-视黄醇复合物输送的血清全反式视黄醇（1）的流入。我们先前已鉴定出选择性RBP4拮抗剂，这些拮抗剂能够解离循环中的RBP4-TTR-视黄醇复合物，降低血清RBP4水平，并在增强视网膜脂褐素生成模型中抑制双视黄醇的合成。然而，选择性RBP4拮抗剂释放的TTR可能与TTR四聚体不稳定化有关，甚至可能引发TTR淀粉样变性。本文描述了双特异性RBP4拮抗剂-TTR四聚体动力学稳定剂的鉴定。突出同分异构体（±）-44对两个靶点均具有适宜的效力，显著降低小鼠血浆RBP4水平，并在基于凝胶的试验中防止TTR聚集。这一新型双特异性化合物类群可能对治疗干性AMD患者尤为重要，因为这些患者通常伴有另一种常见的老年相关共病——老年系统性淀粉样变性，这是一种非遗传性疾病，与野生型TTR错误折叠相关。