Design, synthesis, and biological evaluation of deuterated apalutamide with improved pharmacokinetic profiles. Issue 12 (15th June 2017)

• Record Type: Journal Article
• Authors: Pang, Xuehai; Wang, Yingwei; Chen, Yuanwei
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 12(2017)
• Page Start: 2803
• Page End: 2806
• Publication Date: 2017-06-15
• Subjects: Apalutamide -- Castration-resistant prostate cancer -- AR antagonist -- Deuterium kinetic isotope effect -- Pharmacokinetic; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.04.071
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of deuterated apalutamide were designed and prepared. Compared to its prototype compound18, deuterated analogues19 and21 showed obviously higher plasma concentrations and better PK parameters after oral administration in mice . In rats, N -trideuteromethyl compound19 displayed 1.8-fold peak concentration (Cmax ), and nearly doubled its drug exposure in plasma (AUC0–∞ ) compared to compound18 . Unsurprisingly, compounds18 and19 had similar affinity for AR in vitro . In summary, the deuteration strategy could obviously improve PK parameters of apalutamide.