Metabolic dysfunction-associated steatohepatitis (MASH) has become a serious threat to human health, which exhibited an increasing prevalence globally. Recently, the farnesoid X receptor (FXR) has been identified as a promising strategy for the treatment of MASH by regulating multiple pathogenesis. In this study, a new series of FXR agonists bearing piperidine scaffold was designed to reduce the high lipophilicity of the existing FXR agonists. After comprehensive multiparameter optimization, LZ-007 was discovered as a highly potent FXR agonist with suitable stability in liver microsomes of multiple species. LZ-007 exhibited highly oral bioavailability and targeted tissue exposure in the liver and ileum, while the plasma exposure is low, which might minimize the systemic side effects. Moreover, LZ-007 was significantly up-regulated the expressions of FXR and its downstream genes in the liver and ileum. In MASH model, LZ-007 exerted potent anti-MASH effects by regulating the multiple signal pathways related to lipid metabolism, oxidative stress, inflammation and fibrosis. In a 30-day toxicity study, no apparent adverse effects were observed in LZ-007 treated groups, even at the high doses of 250 and 500 mg/kg. With the positive pharmacodynamics and safety profiles, LZ-007 is worthy of further evaluation as a new anti-MASH agent.

中文翻译：

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带有哌啶支架的新型高效 FXR 激动剂的设计、合成和生物学评价


代谢功能障碍相关脂肪性肝炎 （MASH） 已成为对人类健康的严重威胁，在全球范围内的患病率越来越高。最近，法尼醇 X 受体 （FXR） 已被确定为通过调节多种发病机制治疗 MASH 的一种有前途的策略。在这项研究中，设计了一系列带有哌啶支架的新型 FXR 激动剂，以降低现有 FXR 激动剂的高亲脂性。经过全面的多参数优化，LZ-007 被发现是一种高效的 FXR 激动剂，在多个物种的肝微粒体中具有适当的稳定性。LZ-007 在肝脏和回肠中表现出高度的口服生物利用度和靶向组织暴露，而血浆暴露量低，这可能会最大限度地减少全身副作用。此外，LZ-007 显着上调肝脏和回肠中 FXR 及其下游基因的表达。在 MASH 模型中，LZ-007 通过调节与脂质代谢、氧化应激、炎症和纤维化相关的多个信号通路发挥强大的抗 MASH 作用。在一项为期 30 天的毒性研究中，即使在 250 和 500 mg/kg 的高剂量下，LZ-007 治疗组也没有观察到明显的不良反应。凭借积极的药效学和安全性，LZ-007 作为一种新的抗 MASH 药物值得进一步评估。