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Several down, a few to go: histamine H3 receptor ligands making the final push towards the market?

Introduction: The histamine H3 receptor (H3R) plays a pivotal role in a plethora of therapeutic areas. Blocking the H3R with antagonists/inverse agonists has been postulated to be of broad therapeutic use. Indeed, H3R antagonists/inverse agonists have been extensively evaluated in the clinic. Areas covered: Here, we address new developments, insights obtained and challenges encountered in the clinical evaluations. For recent H3R clinical candidates, the status and results of the corresponding clinical trial(s) will be discussed along with preclinical data. Main findings: In all, it becomes evident that clinical evaluation of H3R antagonists/inverse agonists is characterized by mixed results. On one hand, Pitolisant has successfully passed several Phase II trials and seems to be the most advanced compound in the clinic now, being in Phase III. On the other hand, some compounds (e.g., PF-03654647 and MK-0249) failed at Phase II clinical level for several indications. Expert opinion: A challenging feature in H3R research is the multifaceted role of the receptor at a molecular/biochemical level, which can complicate targeting by small molecules at several (pre)clinical levels. Accordingly, H3R antagonists/inverse agonists require further testing to pinpoint the determinants for clinical efficacy and to aid in the final push towards the market.