Synthesis and biological activity of novel tert-butyl and tert-pentylphenoxyalkyl piperazine derivatives as histamine H3R ligands

• Published in: European journal of medicinal chemistry 2018-05, Vol.152, p.223-234
• Main Authors: Szczepańska, Katarzyna, Karcz, Tadeusz, Mogilski, Szczepan, Siwek, Agata, Kuder, Kamil J., Latacz, Gniewomir, Kubacka, Monika, Hagenow, Stefanie, Lubelska, Annamaria, Olejarz, Agnieszka, Kotańska, Magdalena, Sadek, Bassem, Stark, Holger, Kieć-Kononowicz, Katarzyna
• Format: Article
• Language: English
• Subjects: Anticonvulsants; Histamine H3 receptor; Histamine H3 receptor ligands; Metabolic stability; Molecular docking; Non-imidazole histamine H3R ligands; Piperazine derivatives; Pro-cognitives
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.04.043

As a continuation of our search for novel histamine H3 receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2−25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (Ki = 16.0–120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional H3R antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10,in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in H3R ligands. [Display omitted] •Synthesis of 4N-(hetero) (aryl)substituted piperazine alkyl ethers was performed.•Human histamine H3 receptor affinity was estimated.•The most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure model in mice.•BBB penetration, functional H3R antagonist potency and the pro-cognitive properties for compound 10 was demonstrated.•As well as its in silico and experimental tests of metabolic stability in human liver microsomes was performed.•4-pyridyl-piperazino moiety has been established as a new bioisoteric piperidine replacement in H3R ligands.