Wang Fangying, Jiang Hongxia, Deng Yufang, Yu Jiang, Zhan Miao, Zhao Lifeng, Chen Yuanwei
State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School of Sichuan University, Chengdu 610041, China.
Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710054, China.
Bioorg Med Chem Lett. 2018 Aug 1;28(14):2399-2402. doi: 10.1016/j.bmcl.2018.06.025. Epub 2018 Jun 15.
Vismodegib is an oral and high selective hedgehog (Hh) inhibitor used for the treatment of basal cell carcinoma (BCC). In this work, analogs of Vismodegib with deuterium-for-hydrogen replacement at certain metabolically active sites were prepared and found to have a better pharmacokinetic properties in mice. In particular, deuterated compound SKLB-C2211 obviously altered the blood circulation behavior compared to its prototype, which was demonstrated by significantly prolonged blood circulation half-life time (t) and increased AUC. These results suggested SKLB-C2211 had the potential to be a long-acting inhibitor against Hh signaling pathway, and laid the foundation for the further research of its druggability.
维莫德吉是一种口服的高选择性刺猬蛋白（Hh）抑制剂，用于治疗基底细胞癌（BCC）。在本研究中，制备了在某些代谢活性位点进行氢-氘取代的维莫德吉类似物，并发现其在小鼠体内具有更好的药代动力学性质。特别是，氘代化合物SKLB-C2211与其原型相比，明显改变了血液循环行为，这表现为血液循环半衰期（t）显著延长和曲线下面积（AUC）增加。这些结果表明SKLB-C2211有潜力成为一种针对Hh信号通路的长效抑制剂，并为其成药性的进一步研究奠定了基础。
