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

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.