Histamine H3 receptor (H3R) is largely expressed in the CNS and modulation of the H3R function can affect histamine synthesis and liberation, and modulate the release of many other neurotransmitters. Targeting H3R with antagonists/inverse agonists may have therapeutic applications in neurodegenerative disorders, gastrointestinal and inflammatory diseases. This prompted us to design and synthesize azole-based H3R ligands, i.e. having oxadiazole- or thiazole-based core structures. While ligands of oxadiazole scaffold were almost inactive, thiazole-based ligands were very potent and several exhibited binding affinities in a nanomolar concentration range. Ligands combining 4-cyanophenyl moiety as arbitrary region, para-xylene or piperidine carbamoyl linkers, and/or pyrrolidine or piperidine basic heads were found to be the most active within this series of thiazole-based H3R ligands. The most active ligands were in silico screened for ADMET properties and drug-likeness. They fulfilled Lipinski's and Veber's rules and exhibited potential activities for oral administration, blood-brain barrier penetration, low hepatotoxicity, combined with an overall good toxicity profile.

Design, synthesis, and biological evaluation of novel oxadiazole- and thiazole-based histamine H3R ligands

2019 Spring National Meeting

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