Zheng Lei, Chen Kun, Xie Yifan, Huang Jiaxi, Xia Chuang, Bao Ying-Xia, Bi Huichang, Wang Jigang, Zhou Zhong-Zhen
Innovation Program of Drug Research on Neurological and Metabolic Diseases, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Guangzhou Baiyunshan Pharmaceutical Co. Ltd., Guangzhou Baiyunshan Pharmaceutical General Factory, Guangzhou, China.
Eur J Med Chem. 2024 Nov 5;277:116710. doi: 10.1016/j.ejmech.2024.116710. Epub 2024 Jul 31.
Inflammatory bowel disease (IBD) is a chronic and progressive condition with a significant global burden. Currently, available treatments primarily provide symptomatic relief and retard disease progression, yet they do not offer a cure and are frequently associated with adverse effects. Therefore, the discovery of new targets and therapeutic drugs for IBD is crucial. Phosphodiesterase 4 (PDE4) inhibitors have emerged as promising candidates in the search for effective IBD treatments, although dose-dependent side effects hamper their clinical utility. In this study, building upon heterocyclic biaryl derivatives (TPA16), we designed and synthesized a series of N-substituted indazole-based PDE4D inhibitors, emphasizing improving safety profiles. An enzyme activity screening discovered an optimized compound, LZ-14 (Z21115), which exhibited high PDE4D7 (IC = 10.5 nM) inhibitory activity and good selectivity. More interestingly, LZ-14 has demonstrated promising effects in treating IBD in mouse models by improving the inflammatory response and colon injury. Furthermore, LZ-14 displayed low emetogenic potential in ketamine/xylazine anesthesia mice alternative models.
炎症性肠病（IBD）是一种慢性进行性疾病，在全球造成重大负担。目前，现有的治疗方法主要是缓解症状和延缓疾病进展，但无法治愈，且常常伴有不良反应。因此，发现IBD的新靶点和治疗药物至关重要。磷酸二酯酶4（PDE4）抑制剂已成为寻找有效IBD治疗方法的有希望的候选药物，尽管剂量依赖性副作用限制了它们的临床应用。在本研究中，基于杂环联芳基衍生物（TPA16），我们设计并合成了一系列基于N-取代吲唑的PDE4D抑制剂，重点是改善安全性。酶活性筛选发现了一种优化化合物LZ-14（Z21115），它表现出高PDE4D7（IC = 10.5 nM）抑制活性和良好的选择性。更有趣的是，LZ-14在小鼠模型中通过改善炎症反应和结肠损伤，在治疗IBD方面显示出有希望的效果。此外，LZ-14在氯胺酮/赛拉嗪麻醉小鼠替代模型中显示出低致吐潜力。
