title: Novel flurbiprofen derivatives with improved brain delivery: synthesis, in vitro and in vivo evaluations.
abstract: Tarenflurbil (R-flurbiprofen) was acknowledged as a promising candidate in Alzheimer's disease (AD) therapy. However, the Phase III study of tarenflurbil was extremely restricted by its poor delivery efficiency to the brain. To tackle this problem, the novel carriers for tarenflurbil, racemic flurbiprofen (FLU) derivatives (FLU-D1 and FLU-D2) modified by N,N-dimethylethanolamine-related structures were synthesized and characterized. These derivatives showed good safety level in vitro and they possessed much higher cellular uptake efficiency in brain endothelial cells than FLU did. More importantly, the uptake experiments suggested that they were internalized via active transport mechanisms. Biodistribution studies in rats also illustrated a remarkably enhanced accumulation of these derivatives in the brain. FLU-D2, the ester linkage form of these derivatives, achieved a higher brain-targeting efficiency. Its Cmaxand AUC0-twere enhanced by 12.09-fold and 4.61-fold, respectively compared with those of FLU. Additionally, it could be hydrolyzed by esterase in the brain to release the parent FLU, which might facilitate its therapeutic effect. These in vitro and in vivo results highlighted the improvement of the brain-targeted delivery of FLU by making use of N,N-dimethylethanolamine ligand, with which an active transport mechanism was involved.
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu , Sichuan , People's Republic of China and.
authors.forename: Dan
authors.initials: D
authors.lastname: Zheng
authors.affiliation: b West China Hospital , Sichuan University , Chengdu , Sichuan , People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Shuai
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu , Sichuan , People's Republic of China and.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Li
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu , Sichuan , People's Republic of China and.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu , Sichuan , People's Republic of China and.
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu , Sichuan , People's Republic of China and.
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu , Sichuan , People's Republic of China and.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D003642:Deanol / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D042783:Endothelial Cells / Q000378:metabolism; D005480:Flurbiprofen / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D004337:Drug Carriers; D003642:Deanol; C505522:tarenflurbil; D005480:Flurbiprofen
keywords: Active transport; Alzheimer’s disease; N,N-dimethylethanolamine; brain targeting; flurbiprofen