Synthesis and pharmacological evaluation of some amino-acid-containing cyproheptadine derivatives as dual antagonists of histamine H 1- and leukotriene D 4-receptors

Abstract

A novel series of cyproheptadine derivatives, in which an amino acid or a dipeptide moiety was introduced at the piperidine nitrogen, have been synthesized. The amino acid and dipeptide moieties were taken as part of leukotriene D4 (LTD4) pharmacophore. This modification reduced the H1-antihistamine activity (100–1000-fold) but elevated the anti-LTD4 activity (10–100-fold) of the compounds, as compared with cyproheptadine. As a result, some of the new compounds, especially the α-aminopropionic acid derivatives 4, are well-balanced dual antagonists of histamine and LTD4 with both activities at micromolar range. Radioligand binding studies have confirmed that the new compounds, but not cyproheptadine for LTD4, exert their action through competetive occupation of the receptors. One compound, (S)-2-benzyloxycarbonyl-amino-3-[4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)piperidin-1-yl]propionic acid (4c), was tested in an in vitro guinea-pig asthma model. It exhibits much more potent inhibition (ICS50 = 1.5 μM) against antigen-induced contraction than either terfenadine or FPL55712, the reference drugs. As indicated by an ex vivo binding assay, the drug 4c does not readily pass the blood-brain barrier, and therefore is unlikely to cause sedating side-effects at a therapeutic dose.