Histamine H3 receptor antagonists:: From target identification to drug leads

The successful cloning and functional expression of the histamine H-3 receptor in the late 1990s has greatly facilitated our efforts to identify small molecule, non-imidazole based compounds to permit the evaluation of H-3 antagonists in models of CNS disorders. High-throughput screening identified several series of lead compounds, including a series of imidazopyridines, which led to JNJ-6379490, a compound with high affinity for the human H-3 receptor. Analysis of structural features common to several series of non-imidazole H-3 receptor ligands resulted in a pharmacophore model. This model led to the design of JNJ-5207852, a diamine-based H-3 antagonist with good in vitro and in vivo efficacy but with an undesirable long half-life. However, further modifications of the template provided an understanding of the effect of structural modifications on pharmacokinetic properties, ultimately affording several additional series of compounds including JNJ-10181457, a compound with an improved pharmacokinetic profile. These compounds allowed in vivo pharmacological evaluation to show that H-3 antagonists promote wakefulness, but unlike modafinil and classical psychostimultants, they do not increase locomotor activity or produce any alteration of the EEG power spectral activity in rats. H-3 antagonists also increase extracellular acetylcholine and norepinephrine but not dopamine in rat frontal cortex and show efficacy in various models of learning-memory deficit. In addition, cFos immunoreactivity studies show H-3 antagonists activate neuronal cells in restricted rat brain regions in contrast to widespread activation after modafinil or amphetamine treatment. Therefore, H-3 antagonists are promising clinical candidates for the treatment of excessive day time sleepiness and/or cognitive disorders. (c) 2006 Elsevier Inc. All rights reserved.