期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 14, 页码 2399-2402出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.06.025
关键词
Vismodegib; Hedgehog signaling pathway; Basal cell carcinoma; Deuterated drug; Deuterium-hydrogen replacement; Pharmacokinetic properties
资金
- National Natural Science Foundation of China [81472418]
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(1/2)) and increased AUC(0 ->infinity). 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.
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