Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics,Journal of Medicinal Chemistry

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Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-04-01 , DOI: 10.1021/acs.jmedchem.1c00235
Simone Schierle ₁ , Apirat Chaikuad _{1,

2} , Felix F. Lillich ₁ , Xiaomin Ni _{1,

2} , Stefano Woltersdorf ₁ , Espen Schallmayer ₁ , Beatrice Renelt ₁ , Riccardo Ronchetti ₁ , Stefan Knapp _{1,

2} , Ewgenij Proschak ₁ , Daniel Merk ₁

Affiliation

The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure–activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and in vivo settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.

中文翻译：

Oxaprozin类似物作为具有卓越性能和药代动力学的选择性RXR激动剂

类视黄醇X受体（RXR）是配体激活的转录因子，参与多个调节网络，作为核受体的通用异源二聚体伴侣。尽管在许多病理学中它们具有很高的治疗潜力，但由于目前可用的RXR激动剂遭受异常的亲脂性，不良的药代动力学（PK）和不良影响，因此仅在癌症治疗中开发了RXR靶向。为了克服这些限制并提供改进的RXR配体，我们开发了一种基于非甾体抗炎药奥沙普嗪的新型有效RXR配体化学型。系统的结构-活性关系分析使结构优化朝向低纳摩尔效价，类似于公认的类维生素A。活性最高的衍生物的共晶结构显示出正构结合，并且与目前的RXR激动剂相比，体内分析显示出优异的PK特性。优化的化合物对RXR激活具有高度选择性，并在天然细胞和体内环境中诱导了RXR调控的基因表达，这表明它们是进一步探索RXR的治疗潜力的优秀化学工具。

更新日期：2021-04-22

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