Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders.,Journal of Medicinal Chemistry

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Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-10 , DOI: 10.1021/acs.jmedchem.9b01189
Xiaozheng Dou _{1,

2} , Dinesh Nath _{1,

2} , Henry Shin ₃ , Elmar Nurmemmedov ₄ , Philip C Bourne ₂ , Jian-Xing Ma ₃ , Adam S Duerfeldt _{1,

2}

Affiliation

Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPARα is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an streptozotocin-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogues, which led to the discovery of 4u and related compounds that reach cellular potencies <50 nM and exhibit >2,700-fold selectivity for PPARα over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.

中文翻译：

4-苄氧基-苄基氨基化学型的进化，以提供有效、强效和异构体选择性 PPARα 激动剂作为视网膜疾病的先导。

过氧化物酶体增殖物激活受体α (PPARα) 在视网膜 Müller 细胞、内皮细胞和视网膜色素上皮细胞中表达；PPARα 与遗传或药理学工具的激动作用可改善动物模型中与视网膜疾病相关的炎症、血管渗漏、神经退行性变和新血管形成。因此，PPARα 是治疗糖尿病视网膜病变和年龄相关性黄斑变性的有希望的药物靶点。在此，我们报告了链脲佐菌素诱导的血管渗漏模型（大鼠）中的概念验证体内功效和第一代铅4a（A91）的初步药代动力学评估。此外，我们介绍了第二代类似物的设计、合成和评估，从而发现了4u和相关化合物，其细胞效力 <50 nM，对 PPARα 的选择性比其他 PPAR 异构体高 2,700 倍以上。这些研究确定了一系列候选药物，用于详细的 PK/PD 和临床前评估。

更新日期：2020-03-10

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