Cao Ruolin, Zhang Maoying, Qi Minggang, Zhang Zhen, Morisseau Christophe, Zhou Chunwei, Sun Tianqi, Zhuang Junning, Chen Lu, Xu Cheng, Liu Zhongbo, Hammock Bruce D, Chen Guoliang
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis California 95616, United States.
J Med Chem. 2025 Apr 24;68(8):8729-8767. doi: 10.1021/acs.jmedchem.5c00402. Epub 2025 Apr 4.
The peroxisome proliferator-activated receptor-γ (PPARγ) serves as a pivotal regulator of lipid balance, adipogenesis, and inflammatory processes. PPARγ full agonists display strong curative effects but also serious adverse effects. Here, we found a novel 4-(cyclohexyloxy)phenyl acetate scaffold with partial PPARγ agonist activity, and its structure-activity relationship was studied. We also describe the structure-guided lead optimization of orally bioavailable as a dual modulator of soluble epoxide hydrolase (sEH) and partial PPARγ, which can inhibit Ser273 phosphorylation. In mice, oral administration of at a dose of 5 g/kg resulted in excellent safety; a significant reduction in the negative consequences of lipid accumulation and water-sodium retention; and no gastrointestinal adverse effects, weight gain, or cardiotoxicity. In addition, has shown a better effect than pioglitazone () in type 2 diabetes and nonalcoholic steatohepatitis. Additionally, has demonstrated potent anti-inflammatory and analgesic properties in models of both neuropathic and inflammatory pain.
过氧化物酶体增殖物激活受体γ（PPARγ）是脂质平衡、脂肪生成和炎症过程的关键调节因子。PPARγ 完全激动剂显示出强大的治疗效果，但也有严重的不良反应。在此，我们发现了一种具有部分PPARγ 激动剂活性的新型4-（环己氧基）苯基乙酸酯支架，并对其构效关系进行了研究。我们还描述了作为可溶性环氧化物水解酶（sEH）和部分PPARγ 的双重调节剂的口服生物利用度的结构导向先导优化，其可抑制Ser273磷酸化。在小鼠中，以5 g/kg的剂量口服给药具有极佳的安全性；脂质积累和水钠潴留的负面后果显著减少；且无胃肠道不良反应、体重增加或心脏毒性。此外，在2型糖尿病和非酒精性脂肪性肝炎中，其显示出比吡格列酮更好的效果。此外，在神经性疼痛和炎性疼痛模型中，其已表现出强大的抗炎和镇痛特性。
