1290617-50-3Relevant academic research and scientific papers
Discovery of brain-penetrant, irreversible kynurenine aminotransferase ii inhibitors for schizophrenia
Dounay, Amy B.,Anderson, Marie,Bechle, Bruce M.,Campbell, Brian M.,Claffey, Michelle M.,Evdokimov, Artem,Evrard, Edelweiss,Fonseca, Kari R.,Gan, Xinmin,Ghosh, Somraj,Hayward, Matthew M.,Horner, Weldon,Kim, Ji-Young,McAllister, Laura A.,Pandit, Jayvardhan,Paradis, Vanessa,Parikh, Vinod D.,Reese, Matthew R.,Rong, Suobao,Salafia, Michelle A.,Schuyten, Katherine,Strick, Christine A.,Tuttle, Jamison B.,Valentine, James,Wang, Hong,Zawadzke, Laura E.,Verhoest, Patrick R.
supporting information; experimental part, p. 187 - 192 (2012/04/23)
Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and 13C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structurea€"activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.
A general strategy for the synthesis of cyclic N-aryl hydroxamic acids via partial nitro group reduction
McAllister, Laura A.,Bechle, Bruce M.,Dounay, Amy B.,Evrard, Edelweiss,Gan, Xinmin,Ghosh, Somraj,Kim, Ji-Young,Parikh, Vinod D.,Tuttle, Jamison B.,Verhoest, Patrick R.
, p. 3484 - 3497 (2011/06/24)
We describe a generalized approach to stereocontrolled synthesis of substituted cyclic hydroxamic acids (3-amino-1-hydroxy-3,4-dihydroquinolinones) by selective reduction of substituted 2-nitrophenylalanine substrates. Compounds in this series have antibacterial properties and have also recently been reported as KAT II inhibitors. The key nitrophenyl alanine intermediates are prepared enantioselectively in excellent yield by phase transfer catalyzed alkylation of the corresponding nitrobenzyl bromides. The scope and limitations of the reductive cyclization transformation have been explored with attention to the effects of substitution pattern and electronics on reaction efficiency and byproduct formation. In addition, a novel activated trifluoroethyl ester cyclization strategy has been developed as an alternate approach to the most sterically demanding systems in this series.
