a Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province , Institute of Materia Medica, Zhejiang Academy of Medical Sciences , Hangzhou , PR China.
b School of Basic Science , China Pharmaceutical University , Nanjing , PR China.
J Enzyme Inhib Med Chem. 2019 Dec;34(1):808-817. doi: 10.1080/14756366.2019.1587417.
The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer, inflammation, obesity, and cardiovascular disease. Recently, the discovery of novel BRD4 inhibitors has garnered substantial interest. Starting from scaffold hopping of the reported compound dihydroquinazolinone (PFI-1), a series of coumarin derivatives were designed and synthesised as a new chemotype of BRD4 inhibitors. Interestingly, the representative compounds 13 exhibited potent BRD4 binding affinity and cell proliferation inhibitory activity, and especially displayed a favourable PK profile with high oral bioavailability (F = 49.38%) and metabolic stability (T = 4.2 h), meaningfully making it as a promising lead compound for further drug development.
溴结构域和末端（BET）溴结构域，特别是 BRD4，已被确定为治疗多种人类疾病（如癌症、炎症、肥胖和心血管疾病）的有前途的治疗靶点。最近，新型 BRD4 抑制剂的发现引起了广泛关注。从报道的二氢喹唑啉酮（PFI-1）的骨架跳跃开始，设计并合成了一系列香豆素衍生物，作为 BRD4 抑制剂的新型化学型。有趣的是，代表性化合物 13 表现出很强的 BRD4 结合亲和力和细胞增殖抑制活性，特别是表现出良好的 PK 特性，具有高口服生物利用度（F=49.38%）和代谢稳定性（T=4.2 h），有意义地使其成为进一步药物开发的有前途的先导化合物。
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