E2027 (irsenontrine), a phosphodiesterase 9 inhibitor, enhances cholinergic function when combined with donepezil hydrochloride.

Phosphodiesterase 9 (PDE9) is an enzyme that hydrolyzes cyclic guanosine monophosphate (cGMP)-a second messenger that regulates neuronal plasticity and memory function. PDE9 inhibition has been shown to enhance cognitive function in rodents, underlining the potential of PDE9 inhibitors (PDE9Is) as novel therapeutics for cognitive dysfunction. Considering the critical role of nitric oxide (NO)-cGMP signaling cascade in acetylcholine (ACh) release, the combination of PDE9Is and acetylcholinesterase inhibitors may synergistically elevate ACh levels in the brain.

Discovery of : A Highly Potent, Selective, and CNS Penetrant mGluR Allosteric Agonist.

The low affinity metabotropic glutamate receptor mGluR has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR agonists. Of particular interest is the chromane , a potent (EC 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR compared to not only other mGluRs, but also a broad range of targets.

Mechanistic Multilayer Quantitative Model for Nonlinear Pharmacokinetics, Target Occupancy and Pharmacodynamics (PK/TO/PD) Relationship of D-Amino Acid Oxidase Inhibitor, TAK-831 in Mice.

Purpose: TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) currently under clinical development for schizophrenia. In this study, a mechanistic multilayer quantitative model that parsimoniously connects pharmacokinetics (PK), target occupancy (TO) and D-serine concentrations as a pharmacodynamic (PD) readout was established in mice.

Methods: PK, TO and PD time-profiles were obtained in mice and analyzed by mechanistic binding kinetics model connected with an indirect response model in a step wise fashion.

Assessment of the Target Engagement and D-Serine Biomarker Profiles of the D-Amino Acid Oxidase Inhibitors Sodium Benzoate and PGM030756.

Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids.

γ-Secretase modulators: current status and future directions.

This chapter reviews the current status of γ-secretase modulators, highlighting key compounds by each company involved in the area. The review focuses on the three main chemotypes: acids, imidazoles and related derivatives and natural products. A section on chemical biology and ligand-binding site elucidation studies is also included.

Amphiphysin I phosphorylation on residue threonine 260 in a pentylenetetrazole-induced seizure model.

A method to evaluate kinase inhibitor action was reported [L. Morgan, S.J.

Development of a pentylenetetrazole-induced seizure model to evaluate kinase inhibitor efficacy in the central nervous system.

c-Jun N-terminal kinases (JNKs) are implicated in cell death in neurodegenerative disorders. Therefore, JNK inhibitors could act as neuroprotective agents. To evaluate potential candidates, reproducible and quantitative CNS in vivo models are required.

The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold.

Imidazole-based structures of p38 inhibitors served as a starting point for the design of JNK3 inhibitors. Construction of a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold led to the synthesis of the (S)-enantiomers, which exhibited p38/JNK3 IC50 ratio of up to 10 and were up to 20 times more potent inhibitors of JNK3 than the relevant (R)-enantiomers. The JNK3 inhibitory potency correlated well with inhibition of c-Jun phosphorylation and neuroprotective properties of the compounds in low K+-induced cell death of rat cerebellar granule neurones.