Design,synthesis, and biological evaluation of deuterated apalutamide with improved pharmacokinetic profiles |
| |
| Authors: | Xuehai Pang Yingwei Wang Yuanwei Chen |
| |
| Institution: | 1. Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China;2. University of Chinese Academy of Sciences, Beijing 100049, China;3. Hinova Pharmaceuticals Inc., Suite 301, Rongyao Building B, #5 South KeYuan Road, Chengdu, Sichuan 610041, China;4. Lab of YWChen, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China |
| |
| Abstract: | A series of deuterated apalutamide were designed and prepared. Compared to its prototype compound 18, deuterated analogues 19 and 21 showed obviously higher plasma concentrations and better PK parameters after oral administration in mice. In rats, N-trideuteromethyl compound 19 displayed 1.8-fold peak concentration (Cmax), and nearly doubled its drug exposure in plasma (AUC0–∞) compared to compound 18. Unsurprisingly, compounds 18 and 19 had similar affinity for AR in vitro. In summary, the deuteration strategy could obviously improve PK parameters of apalutamide. |
| |
| Keywords: | Apalutamide Castration-resistant prostate cancer AR antagonist Deuterium kinetic isotope effect Pharmacokinetic |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
