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Review

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

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Pages 175-196 | Received 22 Nov 2017, Accepted 02 Jan 2018, Published online: 15 Jan 2018
 

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 A2A) 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

Supplemental data

Supplemental data for this article can be accessed here.

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.

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