Journal of Medicinal Chemistry p. 2967 - 2987 (2015)
Update date:2022-08-16
Topics:
Wityak, John
McGee, Kevin F.
Conlon, Michael P.
Song, Ren Hua
Duffy, Bryan C.
Clayton, Brent
Lynch, Michael
Wang, Gwen
Freeman, Emily
Haber, James
Kitchen, Douglas B.
Manning, David D.
Ismail, Jiffry
Khmelnitsky, Yuri
Michels, Peter
Webster, Jeff
Irigoyen, MacArena
Luche, Michele
Hultman, Monica
Bai, Mei
Kuok, Iokteng D.
Newell, Ryan
Lamers, Marieke
Leonard, Philip
Yates, Dawn
Matthews, Kim
Ongeri, Lynette
Clifton, Steve
Mead, Tania
Deupree, Susan
Wheelan, Pat
Lyons, Kathy
Wilson, Claire
Kiselyov, Alex
Toledo-Sherman, Leticia
Beconi, Maria
Mu?oz-Sanjuan, Ignacio
Bard, Jonathan
Dominguez, Celia
Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole. (Chemical Presented)
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