Design, synthesis, and biological evaluation of deuterated apalutamide with improved pharmacokinetic profiles

Xuehai Pang; Yingwei Wang; Yuanwei Chen

doi:10.1016/j.bmcl.2017.04.071

Design, synthesis, and biological evaluation of deuterated apalutamide with improved pharmacokinetic profiles

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2803-2806. doi: 10.1016/j.bmcl.2017.04.071. Epub 2017 Apr 26.

Authors

Xuehai Pang¹, Yingwei Wang¹, Yuanwei Chen²

Affiliations

¹ Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China; Hinova Pharmaceuticals Inc., Suite 301, Rongyao Building B, #5 South KeYuan Road, Chengdu, Sichuan 610041, China; Lab of YWChen, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China. Electronic address: ywchen@scu.edu.cn.

PMID: 28478926
DOI: 10.1016/j.bmcl.2017.04.071

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 (C_max), and nearly doubled its drug exposure in plasma (AUC_0-∞) 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: AR antagonist; Apalutamide; Castration-resistant prostate cancer; Deuterium kinetic isotope effect; Pharmacokinetic.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Cell Line, Tumor
Drug Design*
Humans
Mice
Mice, Inbred BALB C
Molecular Structure
Rats
Rats, Sprague-Dawley
Thiohydantoins / administration & dosage
Thiohydantoins / chemistry
Thiohydantoins / pharmacokinetics*

Substances

Thiohydantoins
apalutamide