187217-99-8Relevant articles and documents
Lead Optimization toward Proof-of-Concept Tools for Huntington's Disease within a 4-(1 H -Pyrazol-4-yl)pyrimidine Class of Pan-JNK Inhibitors
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
, p. 2967 - 2987 (2015/04/27)
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)
Nicotinamide Derivatives
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Page/Page column 19-20, (2008/12/06)
The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein the substituents are as defined herein, compositions containing such compounds and the uses of such compounds for the treatment o