The G protein-coupled receptor 35 (GPR35) has been identified as a potential target in the treatment of inflammatory bowel disease (IBD). However, the lack of high and equipotent agonists on both human and mouse GPR35 has limited the in vivo study of GPR35 agonists in mouse models of IBD. In this study, structural modifications to lodoxamide provides a series of high and equivalent agonists on human, mouse, and rat GPR35. These molecules eliminate the species selectivity of human to mouse and rat orthologs that have been prevalent with GPR35 agonists including lodoxamide. The cLogP properties are also optimized to make the compounds more obedient to drug-like rules, yielding compound 4b (cLogP = 2.41), which activates human, mouse or rat GPR35 with EC₅₀ values of 76.0, 63.7 and 77.8 nM, respectively. Oral administration of compound 4b at 20 mg/kg alleviates clinical symptoms of DSS-induced IBD in mice, and is slightly more effective than 5-ASA at 200 mg/kg. In summary, it can serve as a new start point for exploiting more potent GPR35 agonists without species differences for the treatment of IBD, and warrants further study.

G 蛋白偶联受体 35 (GPR35) 已被确定为治疗炎症性肠病 (IBD) 的潜在靶点。然而，人类和小鼠 GPR35 缺乏高效等效激动剂，限制了GPR35 激动剂在 IBD 小鼠模型中的体内研究。在这项研究中，洛度沙胺的结构修饰为人类、小鼠和大鼠 GPR35 提供了一系列高效且等效的激动剂。这些分子消除了人类对小鼠和大鼠直向同源物的物种选择性，这种选择性在 GPR35 激动剂（包括洛度沙胺）中普遍存在。 cLogP 特性也经过优化，使化合物更服从药物样规则，产生化合物4b (cLogP = 2.41)，它激活人、小鼠或大鼠 GPR35，EC ₅₀值分别为 76.0、63.7 和 77.8 nM。口服20mg/kg化合物4b可减轻小鼠中DSS诱导的IBD的临床症状，并且比200mg/kg的5-ASA稍微更有效。总之，它可以作为开发更有效的 GPR35 激动剂而没有物种差异来治疗 IBD 的新起点，值得进一步研究。