biostudies-literatureUnknown3(3)Dounay ABKynurenine 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 (13)C 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 structure-activity relationship invesACS medicinal chemistry letters187-92https://www.ebi.ac.uk/biostudies/studies/S-EPMC4025856biostudies-literatureDiscovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia.PMC4025856Hayward MMDounay ABWang HEvdokimov AMcAllister LAStrick CAReese MRKim JYBechle BMPandit JVerhoest PRSalafia MAHorner WSchuyten KClaffey MMAnderson MCampbell BMEvrard EGhosh SParikh VDRong SZawadzke LEParadis VValentine JFonseca KRGan XTuttle JBfalseDiscovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia.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 (13)C 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 structure-activity relationship inves2012-01-01T00:00:00Z2012 Mar2025-04-04T08:42:01.958Z2019-03-27T01:28:29ZS-EPMC40258562490045510.1021/ml200204m