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: 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
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 3 Issue 3 Pg. 187-92 (Mar 08 2012) ISSN: 1948-5875 [Print] United States
• PMID: 24900455 (Publication Type: Journal Article)