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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.
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-09-03 , DOI: 10.1021/acs.jmedchem.0c00996
Christopher L Cioffi 1 , Parthasarathy Muthuraman 1 , Arun Raja 1 , Andras Varadi 2 , Boglarka Racz 2 , Konstantin Petrukhin 2
Affiliation  

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.

中文翻译:

发现稳定转甲状腺素蛋白四聚体的视黄醇结合蛋白 4 的双特异性拮抗剂:脚手架跳跃、优化和临床前药理学评估作为两种常见年龄相关合并症的潜在疗法。

细胞毒性脂褐素双维甲酸的积累可能导致萎缩性年龄相关性黄斑变性 (AMD) 发病机制。视网膜双类维生素A的合成依赖于血清全反式视黄醇的流入(1) 通过三级视黄醇结合蛋白 4 (RBP4)-甲状腺素运载蛋白 (TTR)-视黄醇复合物递送。我们之前发现了选择性 RBP4 拮抗剂,可在增强的视网膜脂褐质生成模型中解离循环 RBP4-TTR-视黄醇复合物,降低血清 RBP4 水平,并抑制双维甲酸合成。然而,选择性 RBP4 拮抗剂释放 TTR 可能与 TTR 四聚体失稳有关,并可能与 TTR 淀粉样蛋白形成有关。我们在此描述了双特异性 RBP4 拮抗剂-TTR 四聚体动力学稳定剂的鉴定。出色的模拟 (±)- 44对这两种靶标都具有合适的效力,显着降低小鼠血浆 RBP4 水平,并在基于凝胶的测定中防止 TTR 聚集。这类新的双特异性化合物对于干性 AMD 患者的治疗可能特别重要,这些患者有另一种常见的与年龄相关的合并症,即老年系统性淀粉样变性,这是一种与野生型 TTR 错误折叠相关的非遗传性疾病。
更新日期:2020-10-08
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