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

Abstract Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H 3 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 i value of 18 nM. Two para -biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine ( 14 ; K i  = 25 nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane ( 16 ; K i  = 34 nM), classified as antagonists in a cAMP accumulation assay ( IC 50  = 4 and 9 nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED 50 of 2.72 mg/kg and 1.75 mg/kg respectively), and showed high selectivity (hH 4 R vs hH 3 R > 600-fold) and low toxicity (hERG inhibition: IC 50  > 1.70 µM; hepatotoxicity IC 50  > 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.