Histamine H3 receptor antagonists: From target identification to drug leads

The successful cloning and functional expression of the histamine H3 receptor in the late 1990s has greatly facilitated our efforts to identify small molecule, non-imidazole based compounds to permit the evaluation of H3 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 H3 receptor. Analysis of structural features common to several series of non-imidazole H3 receptor ligands resulted in a pharmacophore model. This model led to the design of JNJ-5207852, a diamine-based H3 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 H3 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. H3 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 H3 antagonists activate neuronal cells in restricted rat brain regions in contrast to widespread activation after modafinil or amphetamine treatment. Therefore, H3 antagonists are promising clinical candidates for the treatment of excessive day time sleepiness and/or cognitive disorders.