Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia

• Published in: ACS medicinal chemistry letters Vol. 3; no. 3; pp. 187 - 192
• Main Authors: Dounay, Amy B, Anderson, Marie, Bechle, Bruce M, Campbell, Brian M, Claffey, Michelle M, Evdokimov, Artem, Evrard, Edelweiss, Fonseca, Kari R, Gan, Xinmin, Ghosh, Somraj, Hayward, Matthew M, Horner, Weldon, Kim, Ji-Young, McAllister, Laura A, Pandit, Jayvardhan, Paradis, Vanessa, Parikh, Vinod D, Reese, Matthew R, Rong, SuoBao, Salafia, Michelle A, Schuyten, Katherine, Strick, Christine A, Tuttle, Jamison B, Valentine, James, Wang, Hong, Zawadzke, Laura E, Verhoest, Patrick R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.03.2012; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; hydroxamic acid; KAT II; kynurenine aminotransferase; kynurenic acid; ACID; COVALENT; CRYSTAL-STRUCTURE; CEREBROSPINAL-FLUID; EXTRACELLULAR GLUTAMATE; STRATEGIES; ALIGNMENT; PATHWAY; ELEVATED LEVELS
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml200204m

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–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.