Preclinical Evaluation and Nonhuman Primate Receptor Occupancy Study of F-JNJ-64413739, a PET Radioligand for P2X7 Receptors.

The P2X7 receptor is an adenosine triphosphate-gated ion channel, which is abundantly expressed in glial cells within the central nervous system and in the periphery. P2X7 receptor activation leads to the release of the proinflammatory cytokine IL-1β in the brain, and antagonism of the P2X7 receptor is a novel therapeutic strategy to dampen adenosine triphosphate-dependent IL-1β signaling. PET ligands for the P2X7 receptor will not only be valuable to assess central target engagement of drug candidates but also hold promise as surrogate markers of central neuroinflammation.

PET Imaging of the P2X7 Ion Channel with a Novel Tracer [F]JNJ-64413739 in a Rat Model of Neuroinflammation.

Purpose: The P2X7 receptor, an adenosine triphosphate (ATP)-gated purinoreceptor, has emerged as one of the key players in neuroinflammatory processes. Therefore, developing a positron emission tomography (PET) tracer for imaging of P2X7 receptors in vivo presents a promising approach to diagnose, monitor, and study neuroinflammation in a variety of brain disorders. To fulfill the goal of developing a P2X7 PET ligand as a biomarker of neuroinflammation, [F]JNJ-64413739 has been recently disclosed.

6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3β: discovery of nitrile derivatives with picomolar potency.

We previously disclosed tricylic, 6-carboxylic acid-bearing 4-quinolones as GSK-3β inhibitors. Herein we discuss the optimization of this series to yield a series of more potent 6-nitrile analogs with insignificant anti-microbial activity. Finally, kinase profiling indicated that members of this class were highly specific GSK-3 inhibitors.

Synthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogen synthase kinase-3β.

The synthesis, GSK-3β inhibitory activity, and anti-microbial activity of bicyclic and tricyclic derivatives of the 5,7-diamino-6-fluoro-4-quinolone-3-carboxylic acid scaffold were studied. Kinase selectivity profiling indicated that members of this class were potent and highly selective GSK-3 inhibitors.

2,5-Diketopiperazines as potent and selective oxytocin antagonists 1: Identification, stereochemistry and initial SAR.

This paper covers efforts to discover orally active potent and selective oxytocin antagonists. Screening pooled libraries identified a novel series of 2,5-diketopiperazine derivatives with antagonist activity at the human oxytocin receptor. We report the initial structure-activity relationship investigations and the determination of the stereochemistry of the most potent compounds.

Functional profiling of the proteome with affinity labels.

The analysis of proteomic samples with affinity labels has been firmly established as a tool for the post-genomic researcher. Recent examples highlight the advantages of profiling functionally active members of specific protein families to identify therapeutically relevant protein targets that have escaped normal physiological regulation leading to increased or decreased activity. This dysregulation may result from any number of biological changes that modulate a protein's activity; for example, post-translational modifications of the protein or an imbalance between the protein and its endogenous inhibitor(s).