Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia
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- 作者：Amy B. Dounay ; Marie Anderson ; Bruce M. Bechle ; Brian M. Campbell ; Michelle M. Claffey ; Artem Evdokimov ; Edelweiss Evrard ; Kari R. Fonseca ; Xinmin Gan ; Somraj Ghosh ; Matthew M. Hayward ; Weldon Horner ; Ji-Young Kim ; Laura A. McAllister ; Jayvardhan Pandit ; Vanessa Paradis ; Vinod D. Parikh ; Matthew R. Reese ; SuoBao Rong ; Michelle A. Salafia ; Katherine Schuyten ; Christine A. Strick ; Jamison B. Tuttle ; James Valentine ; Hong Wang ; Laura E. Zawadzke ; Patrick R. Verhoest
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：March 8, 2012
- 年：2012
- 卷：3
- 期：3
- 页码：187-192
- 全文大小：329K
- 年卷期：v.3,no.3(March 8, 2012)
- ISSN：1948-5875
文摘
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 structure鈥揳ctivity 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.