Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator
Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator
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异恶唑型 FXR 激动剂的结构引导修饰：鉴定有效且口服生物可利用的 FXR 调节剂
DOI：
10.1016/j.ejmech.2020.112910
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发表时间：
2021-01-01
影响因子：
6.7
通讯作者：
Xiang, Hua
中科院分区：
文献类型：
--
作者：
Luo, Guoshun;Lin, Xin;Xiang, Hua
法尼醇X受体（FXR）激动剂正在成为用于治疗各种代谢疾病的潜在治疗剂，因为它们对胆汁酸、脂质和葡萄糖稳态显示出多种作用。虽然类固醇奥贝胆酸，一个完整的FXR激动剂，最近被批准，几个副作用可能是由于不足的药理学选择性阻碍其进一步的临床应用。因此，以部分方式激活FXR在新型FXR调节剂的开发中至关重要。我们专注于异恶唑型FXR激动剂（FXR的常见非甾体激动剂）的努力，通过LJN452的结构简化发现了一系列带有芳基脲部分的新型FXR激动剂（第2阶段）。令人鼓舞的是，发现化合物11k是有效的FXR激动剂，其在基于细胞的FXR反式激活测定中表现出类似的FXR激动效力，但与完全激动剂GW 4064和LJN452相比最大功效较低。广泛的体外评价进一步证实了11k在细胞FXR依赖性基因调节中的部分功效，并揭示了其降脂活性。更重要的是，在小鼠中口服给予11k表现出期望的药代动力学特征，导致有希望的体内FXR激动活性。(C)2020 Elsevier Masson SAS。All rights reserved.
Farnesoid X receptor (FXR) agonists are emerging as potential therapeutics for the treatment of various metabolic diseases, as they display multiple effects on bile acid, lipid, and glucose homeostasis. Although the steroidal obeticholic acid, a full FXR agonist, was recently approved, several side effects probably due to insufficient pharmacological selectivity impede its further clinical application. Activating FXR in a partial manner is therefore crucial in the development of novel FXR modulators. Our efforts focusing on isoxazole-type FXR agonists, common nonsteroidal agonists for FXR, led to the discovery a series of novel FXR agonists bearing aryl urea moieties through structural simplification of LJN452 (phase 2). Encouragingly, compound 11k was discovered as a potent FXR agonist which exhibited similar FXR agonism potency but lower maximum efficacy compared to full agonists GW4064 and LJN452 in cell-based FXR transactivation assay. Extensive in vitro evaluation further confirmed partial efficacy of 11k in cellular FXR-dependent gene modulation, and revealed its lipid-reducing activity. More importantly, orally administration of 11k in mice exhibited desirable pharmacokinetic characters resulting in promising in vivo FXR agonistic activity. (C) 2020 Elsevier Masson SAS. All rights reserved.