Design, synthesis and biological evaluation of deuterated Vismodegib for improving pharmacokinetic properties. Issue 14 (1st August 2018)

• Record Type: Journal Article
• Authors: Wang, Fangying; Jiang, Hongxia; Deng, Yufang; Yu, Jiang; Zhan, Miao; Zhao, Lifeng; Chen, Yuanwei
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 14(2018)
• Page Start: 2399
• Page End: 2402
• Publication Date: 2018-08-01
• Subjects: Vismodegib -- Hedgehog signaling pathway -- Basal cell carcinoma -- Deuterated drug -- Deuterium-hydrogen replacement -- Pharmacokinetic properties; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.06.025
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: SKLB-C2211 has prolonged blood circulation half-life time (t1/2) and increased AUC. Three deuterated analogues produced greater AUC0→t than Vismodegib. SKLB-C2211 is potential to be a long-acting inhibitor against Hh signaling pathway. Abstract: 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 (t1/2 ) and increased AUC0→∞ . 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.