title: Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia.
abstract: 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 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.
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Dounay
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Marie
authors.initials: M
authors.lastname: Anderson
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Bechle
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Campbell
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Claffey
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Artem
authors.initials: A
authors.lastname: Evdokimov
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Edelweiss
authors.initials: E
authors.lastname: Evrard
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Kari R
authors.initials: KR
authors.lastname: Fonseca
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Gan
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Somraj
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hayward
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Weldon
authors.initials: W
authors.lastname: Horner
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Laura A
authors.initials: LA
authors.lastname: McAllister
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Paradis
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Vinod D
authors.initials: VD
authors.lastname: Parikh
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reese
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: SuoBao
authors.initials: S
authors.lastname: Rong
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Salafia
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Schuyten
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Strick
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jamison B
authors.initials: JB
authors.lastname: Tuttle
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: James
authors.initials: J
authors.lastname: Valentine
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Zawadzke
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
keywords: KAT II; hydroxamic acid; kynurenic acid; kynurenine aminotransferase