title: Several down, a few to go: histamine H3 receptor ligands making the final push towards the market?
abstract: BACKGROUND
  The histamine H(3) receptor (H(3)R) plays a pivotal role in a plethora of therapeutic areas. Blocking the H(3)R with antagonists/inverse agonists has been postulated to be of broad therapeutic use. Indeed, H(3)R antagonists/inverse agonists have been extensively evaluated in the clinic.
  
  
  METHODS
  Here, we address new developments, insights obtained and challenges encountered in the clinical evaluations. For recent H(3)R clinical candidates, the status and results of the corresponding clinical trial(s) will be discussed along with preclinical data.
  
  
  RESULTS
  In all, it becomes evident that clinical evaluation of H(3)R 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.
  
  
  CONCLUSIONS
  A challenging feature in H(3)R 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, H(3)R antagonists/inverse agonists require further testing to pinpoint the determinants for clinical efficacy and to aid in the final push towards the market.
authors: VU University Amsterdam, Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Exact Sciences, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
authors: Sebastiaan
authors: S
authors: Kuhne
authors: Maikel
authors: M
authors: Wijtmans
authors: Herman D
authors: HD
authors: Lim
authors: Rob
authors: R
authors: Leurs
authors: Iwan J P
authors: IJ
authors: de Esch
mesh_terms: D017326:Clinical Trials, Phase III as Topic; D054314:Drug Inverse Agonism; D006632:Histamine / Q000502:physiology*; D017442:Histamine Agonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006633:Histamine Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008024:Ligands; D058990:Molecular Targeted Therapy; D018100:Receptors, Histamine H3 / Q000378:metabolism*
chemical_list: D017442:Histamine Agonists; D006633:Histamine Antagonists; D008024:Ligands; D018100:Receptors, Histamine H3; D006632:Histamine