Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors were reported to be novel anti-IBD agents, but their clinical use was hampered by side effects such as emesis and nausea. Herein, structure-based discovery of natural mangostanin (1) targeting the M-pocket resulted in the novel and potent PDE4 inhibitor 22d (IC₅₀ = 3.5 nM) and favorable physico-chemical properties. X-Ray study revealed that 22d interacted tightly with the M-pocket and maintained the key interactions between PDE4 and roflumilast. Worthy to note that compounds 22d and our previously reported 4e and 18a, originating from mangostanin, all caused no emesis on beagle dogs at the oral dose of 10 mg/kg, confirming the safety superiority of scaffold in mangostanin derivatives over that in positive roflumilast. Finally, administration of 22d (5.0 mg/kg, twice-daily) exhibited comparable anti-IBD effects to the positive control dipyridamole (25.0 mg/kg, twice-daily) in the dextran sulfate sodium (DSS)-induced IBD mice model, indicating its potential as a novel anti-IBD agent.

炎症性肠病 (IBD) 是具有反复肠黏膜炎症的慢性疾病，其医疗需求仍未得到满足。据报道，PDE4 抑制剂是新型抗 IBD 药物，但其临床应用受到呕吐和恶心等副作用的阻碍。在此，基于结构的天然山竹素 ( 1 ) 靶向 M 口袋的发现产生了新型有效的 PDE4 抑制剂22d (IC ₅₀  = 3.5 nM) 和良好的物理化学性质。X 射线研究表明，22d与 M-pocket 紧密相互作用，并保持 PDE4 和罗氟司特之间的关键相互作用。值得注意的是，化合物22d和我们之前报道的4e和18a, 来源于山竹素, 在比格犬口服 10 mg/kg 剂量时均未引起呕吐, 证实了山竹素衍生物支架相对于阳性罗氟司特的安全性优越性。最后，在葡聚糖硫酸钠 (DSS) 诱导的 IBD 小鼠模型中，给予22d （5.0 mg/kg，每天两次）与阳性对照双嘧达莫（25.0 mg/kg，每天两次）表现出相当的抗 IBD 效果，表明其作为新型抗 IBD 药物的潜力。