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.

By use of parallel chemistry coupled with physicochemical property design, a series of selective κ opioid antagonists have been discovered. The parallel chemistry strategy utilized key monomer building blocks to rapidly expand the desired SAR space. The potency and selectivity of the in vitro κ antagonism were confirmed in the tail-flick analgesia model. This model was used to build an exposure-response relationship between the κ K(i) and the free brain drug levels. This strategy identified 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242, which entered phase 1 clinical testing and has demonstrated target engagement in healthy volunteers.

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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. KEYWORDS: kynurenine amino transferase, kynurenic acid, aryl hydrocarbon receptor, irreversible inhibition, hydroxamic acid, dose response modeling, in vivo microdialysis, schizophrenia T he kynurenine amino transferase (KAT) class of pyridoxal phosphate (PLP)-dependent transaminases catalyzes the cyclization of L-kynurenine to kynurenic acid (KYNA) in the Ltryptophan metabolic pathway. 1,2 Recently, KYNA has been shown to agonize the arylhydrocarbon receptor (AHR), a nuclear protein involved in gene transcription and other cellular regulatory functions. 3 Additionally, a burgeoning body of research implicates KYNA in a range of neurological disorders due to its antagonism of the α7 nicotinic acetylcholine receptor and the N-methyl-D-aspartate (NMDA) receptor. 4,5 Elevated levels of KYNA have been found in the cerebral spinal fluid (CSF) and postmortem brain tissue of schizophrenics. 6−8 Furthermore, individuals with bipolar disorder have also been found to have increased levels of KYNA in the CSF. 9 Decreasing central KYNA levels in afflicted individuals may therefore provide therapeutic benefit for treating these and other psychiatric and neurological disorders. 10,11 Among the four homologous members of the KAT family, KAT II is largely responsible for centrally produced KYNA, thereby emerging as an attractive target for medicinal chemists. 12 As such, recent articles have reported both reversible and irreversible KAT II inhibitors. 13−16 One useful scaffold is hydroxamate 1, a centrally active and irreversible inhibitor of KAT II. 14,17 Preliminary structure−activity relationship (SAR) indicated that substituents were better tolerated on C6 and C7, whereas potency losses were observed with substitution on C5 and C8 (Figure 1). This SAR was supported by the crystal structure, which showed that positions 6 and 7 are oriented toward a solvent-exposed region in the enzyme. 14 In contrast, positions 5 and 8 are directed toward the walls of the binding pocket. As a consequence of these findings, a broad range of analogues were designed to assess the SAR of this series. 14,15 This communication focuses on key analogues that led to the discovery of substantial potency-enhancing interactions with human KAT II.