Synthesis and pharmacological evaluation of some amino-acid-containing cyproheptadine derivatives as dual antagonists of histamine H1- and leukotriene D4-receptors

Article abstract of DOI:10.1016/S0223-5234(97)87535-6

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 competitive 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 (IC₅₀ = 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.