6328-59-2Relevant academic research and scientific papers
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)
Pyrimidines. 7. A Study of the Chlorination of Pyrimidines with Phosphorus Oxychloride in the Presence of N,N-Dimethylaniline
Gershon, Herman,Grefig, Anthony T.
, p. 1161 - 1167 (2007/10/02)
The chlorination of 6-trifluoromethyluracils by phosphorus oxychloride in the presence of N,N-dimethylaniline was studied and compared with results obtained with 6-methyluracils. 6-Trifluoromethyluracils and its 5-chloro analog afforded moderate yields of the di- and trichloropyrimidines, accompanied by good yields of the 2-N-methylanilino by-products, after a 3-hour reaction time.After 24 hours, the 2-N-methylanilinopyrimidines were the primary or sole products.A small yield of 2,4-bis(N-methylanilino)-6-trifluoromethylpyrimidine was also obtained.The 6-methyluracils afforded high yields of the di- and trichloropyrimidines, after 3 and 24 hours, along with minor amounts of the 2-N-methylanilino by-products.After 48 hours, the proportion of 2,4-dichloro-6-methylpyrimidine decreased, and the 2-N-methylanilino product increased. 2-Chloro-4-methylanilino-6-methylpyrimidine and bis(2-N-methylanilino)-6-methylpyrimidine were also formed in small amounts.The chlorination products from 5-chloro-6-methyluracil remained constant over 188 hours of reaction time. It appears that the Π electron distribution around the ring, as influenced by the substituents, controls the course of the chlorination and by-product formation.Since the amination by a tertiary amine is a type of Hoffmann reaction, the presence of the chlorine in 5 position of the ring adds steric hindrance and thus enhances the regiospecificity of the formation of by-products.
