Progress in the development of histamine H₃ receptor antagonists/inverse agonists: a patent review (2013-2017)

ABSTRACT

Introduction: Since years, ligands blocking histamine H₃ receptor (H₃R) activity (antagonists/inverse agonists) are interesting targets in the search for new cures for CNS disorders. Intensive works done by academic and pharmaceutical company researchers have led to many potent and selective H₃R antagonists/inverse agonists. Some of them have reached to clinical trials.

Areas covered: Patent applications from January 2013 to September 2017 and the most important topics connected with H₃R field are analysed. Espacenet, Patentscope, Pubmed, GoogleScholar or Cochrane Library online databases were principially used to collect all the materials.

Expert opinion: The research interest in histamine H₃R field is still high although the number of patent applications has decreased during the past 4 years (around 20 publications). Complexity of histamine H₃R biology e.g. many isoforms, constitutive activity, heteromerization with other receptors (dopamine D₂, D₁, adenosine A_2A) and pharmacology make not easy realization and evaluation of therapeutic potential of anti-H₃R ligands. First results from clinical trials have verified potential utility of histamine H₃R antagonist/inverse agonists in some diseases. However, more studies are necessary for better understanding of an involvement of the histaminergic system in CNS-related disorders and helping more ligands approach to clinical trials and the market.

Lists of abbreviations: hAChEI – human acetylcholinesterase inhibitor; hBuChEI – human butyrylcholinesterase inhibitor; hMAO – human monoamine oxidase; MAO – monoamine oxidase

KEYWORDS:

• Histamine H₃ receptor
• histamine H₃ antagonists/inverse agonists
• patent applications
• clinical trials
• Wakix
• multitarget directed ligands
• radiolabelled ligands
• heteromers

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Article highlights

1. Patent applications published on histamine H₃ receptor antagonists/inverse agonists from 2013 (January) to 2017 (September) were reviewed.

2. There is a decline in interest in patenting new H₃ ligands (20 patent applications in the past 4 years) but not in histamine H₃ receptor field (still high number of published articles >300)

3. The most important topics from the primary literature are multitarget histamine H₃ receptor ligands, radiolabelled histamine H₃ ligands, histamine H₃ receptor heteromers, results from clinical studies, and the first histamine H₃ drug on the market

4. As shown so far by clinical trials anti-H₃ receptor ligands were not proven to be promising candidates for the treatment of AD, ADHD, CIAS or allergic rhinitis in humans (lack of effectiveness or superiority compared with current treatment)

5. Appeared Wakix - the first H₃ receptor drug for the treatment of narcolepsy

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper has been funded by Narodowe Centrum Nauki grant DEC-2011/02/A/NZ4/00031 and DEC-2016/23/B/NZ7/02327.