title: Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing Interactions.
abstract: A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure-activity relationships (SAR) in conjunction with X-ray crystallography led to the discovery of hydroxamate 4, a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of k inact/K i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles.
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Medicinal 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 Medicinal 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 Medicinal 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 Medicinal 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 Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chang
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Medicinal 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 Medicinal 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 Medicinal 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 Medicinal 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 Medicinal 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 Medicinal 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 Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Larry C
authors.initials: LC
authors.lastname: James
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Medicinal 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 Medicinal 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 Medicinal 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 Medicinal 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 Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Rago
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Medicinal 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 Medicinal 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 Medicinal 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 Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
keywords: aryl hydrocarbon receptor; dose response modeling; hydroxamic acid; in vivo microdialysis; irreversible inhibition; kynurenic acid; kynurenine amino transferase; schizophrenia