Biphenyloxy-alkyl-piperidine and azepane derivatives as histamine H3 receptor ligands


Bioorganic & Medicinal Chemistry


Dorota Lazewska (a, Maria Kaleta(a, J. Stephan Schwed(b, Tadeusz Karcz(a, Szczepan Mogilski(c, Gniewomir Latacz(a, Agnieszka Olejarz(a, AgataSiwek(d, Monika Kubacka(c, Annamaria Lubelska(a, Ewelina Honkisz(a, Jadwiga Handzlik(a, Barbara Filipek(c, HolgerStark(b, Katarzyna Kieć-Kononowicz(a



Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H3 receptor. Two series of compounds were obtained with a meta- and a para-biphenyl moiety. The alkyl chain spacer contained five and six carbon atoms. The highest affinity among all compounds was shown by 1-(6-(3-phenylphenoxy)hexyl)azepane (13) with a Ki value of 18 nM. Two para-biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine (14; Ki = 25 nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane (16; Ki = 34 nM), classified as antagonists in a cAMP accumulation assay (IC50 = 4 and 9 nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED50 of 2.72 mg/kg and 1.75 mg/kg respectively), and showed high selectivity (hH4R vs hH3R > 600-fold) and low toxicity (hERG inhibition: IC50 > 1.70 µM; hepatotoxicity IC50 > 12.5 µM; non-mutagenic up to 10 µM). Furthermore, the metabolic stability was evaluated in vitro on human liver microsomes (HLMs) and/or rat liver microsomes (RLMs). Metabolites produced were analyzed and tentatively identified by UPLC-MS techniques. The results demonstrated easy hydroxylation of the biphenyl ring.

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