Discovery of novel PDE4 inhibitors targeting the M-pocket from natural mangostanin with improved safety for the treatment of Inflammatory Bowel Diseases
Discovery of novel PDE4 inhibitors targeting the M-pocket from natural mangostanin with improved safety for the treatment of Inflammatory Bowel Diseases
复制标题
发现针对天然山竹素 M 袋的新型 PDE4 抑制剂，提高治疗炎症性肠病的安全性
DOI：
10.1016/j.ejmech.2022.114631
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Xixin He
中科院分区：
文献类型：
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作者：
Haobai Liu;Quan Wang;Yue Huang;Jinhui Deng;Xi Xie;Jiaqi Zhu;Yijun Yuan;Yue-Ming He;Yi-You Huang;Hai-Bin Luo;Xixin He
炎症性肠病（IBD）是具有反复肠粘膜炎症的慢性疾病，其仍然未满足医疗需求。PDE 4抑制剂是一种新型的抗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，基于结构的发现天然mangostanin（1）靶向M-口袋导致了新的和有效的PDE 4 crossor 22 d（IC 50 = 3.5 nM）和有利的物理化学性质。X-射线研究表明22 d与M-口袋紧密结合，并维持了PDE 4与罗氟司特之间的关键相互作用。值得注意的是，化合物22 d和我们先前公开的4 e和18 a，来源于芒果苷，在口服剂量为10 mg/kg时均未引起比格犬呕吐，证实了芒果苷衍生物中的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22 d（5.0 mg/kg，每日两次）显示出与阳性对照双嘧达莫（25.0 mg/kg，每日两次）相当的抗IBD效果，表明其作为新型抗IBD剂的潜力。
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 inhibitor22d(IC50= 3.5 nM) and favorable physico-chemical properties. X-Ray study revealed that22dinteracted tightly with the M-pocket and maintained the key interactions between PDE4 and roflumilast. Worthy to note that compounds22dand our previously reported4eand18a, 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 of22d(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.