Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H 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 K value of 18nM. Two para-biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine (14; K=25nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane (16; K=34nM), classified as antagonists in a cAMP accumulation assay (IC=4 and 9nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED of 2.72mg/kg and 1.75mg/kg respectively), and showed high selectivity (hHR vs hHR>600-fold) and low toxicity (hERG inhibition: IC>1.70µM; hepatotoxicity IC>12.5µM; non-mutagenic up to 10µM). 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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