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

Abstract

Since years, ligands blocking histamine H receptor (HR) 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 HR 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 HR 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 HR field is still high although the number of patent applications has decreased during the past 4 years (around 20 publications). Complexity of histamine HR biology e.g. many isoforms, constitutive activity, heteromerization with other receptors (dopamine D, D, adenosine A) and pharmacology make not easy realization and evaluation of therapeutic potential of anti-HR ligands. First results from clinical trials have verified potential utility of histamine HR 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.

Histamine H3 receptor density is negatively correlated with neural activity related to working memory in humans

“…Thus, extensive preclinical studies have assessed the role of H 3 receptors in working memory. However, very few such studies have been conducted in humans, and the published clinical studies of H 3 receptor antagonist/inverse agonists have shown the mixed results of cognitive improvements in neuropsychiatric diseases ([ 4 , 5 ] for review). For example, some studies reported the positive effects of H 3 receptor drugs in episodic memory in Alzheimer’s disease, while others found no beneficial effects examined by various drugs in different diseases [ 5 ].…”

“…However, very few such studies have been conducted in humans, and the published clinical studies of H 3 receptor antagonist/inverse agonists have shown the mixed results of cognitive improvements in neuropsychiatric diseases ([ 4 , 5 ] for review). For example, some studies reported the positive effects of H 3 receptor drugs in episodic memory in Alzheimer’s disease, while others found no beneficial effects examined by various drugs in different diseases [ 5 ]. These unclear therapeutic effects may come from the complex biology and pharmacology of H 3 receptor, such as the heterogeneity of isoforms and the different profile of drug activity (full agonists, partial agonists, neutral antagonists, inverse agonists and protean ligands) [ 5 ].…”

“…For example, some studies reported the positive effects of H 3 receptor drugs in episodic memory in Alzheimer’s disease, while others found no beneficial effects examined by various drugs in different diseases [ 5 ]. These unclear therapeutic effects may come from the complex biology and pharmacology of H 3 receptor, such as the heterogeneity of isoforms and the different profile of drug activity (full agonists, partial agonists, neutral antagonists, inverse agonists and protean ligands) [ 5 ].…”

Neuronal histamine and the memory of emotionally salient events

“…We believe that the complex cytoarchitectonic, arrangement and distribution of histamine receptors in different brain regions is responsible for some of the apparently controversial mnemonic effects of, for instance, H 3 receptor antagonists. Pitolisant , an H 3 antagonist, is a newly marketed compound for the treatment of narcolepsy (Kollb‐Sielecka et al, 2017), and preclinical and clinical trials have suggested the potential utility of this class of drugs in neuropsychiatric diseases (Łażewska and Kieć‐Kononowicz, 2018). Dysfunctional fear responses have a crucial role in many mental disorders, and new insights suggest that drug interventions, for example, propranolol , during the reconsolidation of reactivated fear memories may increase the efficacy of therapeutic interventions (Kindt et al, 2009).…”

Conformational Restriction of Histamine with a Rigid Bicyclo[3.1.0]hexane Scaffold Provided Selective H3 Receptor Ligands

“…Much effort has been devoted to developing potent and selective H 3 R inhibitors (antagonists/inverse agonists) [ 3 , 4 , 5 ], and pitolisant ( 2 , Figure 1 ) was recently authorized in Europe as a medicine for treating narcolepsy with or without cataplexy [ 6 ]. Further research is needed to better understand the functions of the histaminergic system in CNS-related disorders and to advance useful H 3 antagonists into clinical trials and the market [ 7 ].…”