Biphenyloxy-alkyl-piperidine and azepane derivatives as histamine H3 receptor ligands.
Bioorg Med Chem
; 25(20): 5341-5354, 2017 10 15.
Article
em En
| MEDLINE
| ID: mdl-28797771
ABSTRACT
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 18nM. Two para-biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine (14; Ki=25nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane (16; Ki=34nM), classified as antagonists in a cAMP accumulation assay (IC50=4 and 9nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED50 of 2.72mg/kg and 1.75mg/kg respectively), and showed high selectivity (hH4R vs hH3R>600-fold) and low toxicity (hERG inhibition IC50>1.70µM; hepatotoxicity IC50>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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Azepinas
/
Receptores Histamínicos H3
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2017
Tipo de documento:
Article