Ren Qiang, Chen Ya, Zhou Zongtao, Cai Zongyu, Jiao Shixuan, Huang Wanqiu, Wang Bin, Chen Siliang, Wang Wenxin, Cao Zhijun, Yang Zhongcheng, Deng Liming, Hu Lijun, Zhang Luyong, Li Zheng
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
J Med Chem. 2023 May 11;66(9):6082-6104. doi: 10.1021/acs.jmedchem.2c01918. Epub 2023 Apr 20.
The prevalence of nonalcoholic steatohepatitis (NASH) is increasing rapidly worldwide, and NASH has become a serious problem for human health. Recently, the selective activation of the intestinal farnesoid X receptor (FXR) was considered as a more promising strategy for the treatment of NASH with lesser side effects due to reduced systemic exposure. Moreover, the inhibition of intestinal fatty acid binding protein 1 (FABP1) alleviated obesity and NASH by reducing dietary fatty acid uptake. In this study, the first-in-class intestinal restricted FXR and FABP1 dual-target modulator ZLY28 was discovered by comprehensive multiparameter optimization studies. The reduced systemic exposure of ZLY28 might provide better safety by decreasing the on- and off-target side effects in vivo. In NASH mice, ZLY28 exerted robust anti-NASH effects by inhibiting FABP1 and activating the FXR-FGF15 signaling pathway in the ileum. With the above attractive efficacy and preliminary safety profiles, ZLY28 is worthy of further evaluation as a novel anti-NASH agent.
非酒精性脂肪性肝炎（NASH）在全球范围内的患病率正在迅速上升，并且NASH已成为人类健康的一个严重问题。最近，由于全身暴露减少，肠道法尼醇X受体（FXR）的选择性激活被认为是一种更有前景的治疗NASH的策略，副作用较小。此外，抑制肠道脂肪酸结合蛋白1（FABP1）可通过减少膳食脂肪酸摄取来减轻肥胖和NASH。在本研究中，通过全面的多参数优化研究发现了首个肠道限制性FXR和FABP1双靶点调节剂ZLY28。ZLY28全身暴露的减少可能通过降低体内的靶向和脱靶副作用而提供更好的安全性。在NASH小鼠中，ZLY28通过抑制FABP1并激活回肠中的FXR-FGF15信号通路发挥强大的抗NASH作用。凭借上述有吸引力的疗效和初步安全性，ZLY28作为一种新型抗NASH药物值得进一步评估。
