A NOVEL, BRAIN PENETRANT KAT-II INHIBITOR, KYN-5356, REDUCES BRAIN KYNURENIC ACID LEVELS AND ENHANCES GLUTAMATERGIC AND CHOLINERGIC TRANSMISSION

Background

Dysregulation of the kynurenine pathway of tryptophan degradation has been implicated in a number of psychiatric and neurological disorders. In the brain, the enzyme kynurenine aminotransferase II (KAT-II) is critical for the conversion of Lkynurenine (L-KYN) to kynurenic acid (KYNA). KYNA, in turn, is an endogenous inhibitor of nicotinic alpha-7 and NMDA receptors, both of which are critical for cognition. Elevated KYNA levels have been consistently reported in the brain and cerebrospinal fluid (CSF) of individuals with schizophrenia and may impair cognitive function in the disease. Preclinical data show that KYNA bi-directionally modulates cognition, with increased KYNA impairing and reduced KYNA improving cognition. Thus, targeted inhibition of KAT-II may have beneficial effects on cognitive function in humans. KYN-5356 is a novel, potent, brainpenetrant, reversible, and selective KAT-II inhibitor in development for Cognitive Impairment Associated with Schizophrenia (CIAS). Here, we present preclinical proof of concept data evaluating the effect of KYN-5356 on KYNA levels and on neurotransmitter systems relevant for cognition.

Methods

Studies were conducted in cynomolgus monkeys and marmosets. The effect of systemic administration of KYN-5356 on KYNA levels was assessed following exogenous administration of L-KYN. Acetylcholine levels were measured in the hippocampus by in vivo microdialysis. The ability of KYN-5356 to enhance cholinergic transmission was also evaluated by electroencephalography (EEG) using the scopolamine reversal model.

Results

KYN-5356 showed adequate bioavailability, brain penetration and a favorable temporal pharmacokinetic profile. As expected, L-KYN administration significantly increased brain and CSF KYNA. KYN-5356 dose-dependently reduced the KYNA/L-KYN ratio in hippocampus and prefrontal cortex, by as much as 50% at the highest dose tested. In separate experiments, a microdialysis probe was inserted in the hippocampus of cynomolgus monkeys. Local infusion of KYN-5356 produced a robust and steady increase in extracellular acetylcholine levels. To assess impact on functional networks, animals were implanted with EEG electrodes. KYN-5356 strongly increased cognitively relevant alpha and beta band activity. Consistent with preclinical and clinical studies, scopolamine, a potent muscarinic blocker, produced a significant increase in delta and theta activity, and KYN-5356 significantly attenuated its effect. Specifically, the effect of scopolamine on delta activity was reduced by more than 50%, while the effect on theta band was nearly completely blocked. This shows that KYN-5356 robustly enhances cholinergic transmission, suggesting that the effect of the drug is not limited to disinhibition of alpha-7 nicotinic receptors.

Discussion

KYN-5356 is a potent, brain-penetrant small molecule suitable for clinical development. KYN-5356 effectively and dose-dependently reduced KYNA levels in the brain. We elucidated a multimodal mechanism of action for KYN-5356 with neurochemical and electrophysiological effects indicative of enhanced cholinergic and glutamatergic transmission. Thus, KYN-5356 is a highly suitable candidate for the treatment of cognitive dysfunction in a range of psychiatric and neurological disorders. A first in human clinical study with KYN-5356 was recently completed, and the compound is currently being evaluated in a proof of concept study in CIAS.