1290617-52-5Relevant articles and documents
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.
