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

• Published in: European journal of medicinal chemistry Vol. 32; no. 2; pp. 95 - 102
• Main Authors: Zhang, MQ, van de Stolpe, A, Zuiderveld, OP, Timmerman, H
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 1997; Elsevier
• Subjects: antiasthmatic activity; antihistamine activity; Chemistry, Medicinal; drug design; dual antagonist; H 1-receptor; in vitro asthma model; leukotriene D 4 antagonist; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; dual antagonist; H 1-receptor; in vitro asthma model; antiasthmatic activity; drug design; antihistamine activity; leukotriene D 4 antagonist; leukotriene D-4 antagonist; H-1-receptor; ANTIHISTAMINES; SERIES; ANALOGS; ASTHMA; AGENTS
• ISSN: 0223-5234; 1768-3254
• 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 D 4 (LTD 4) pharmacophore. This modification reduced the H 1-antihistamine activity (100–1000-fold) but elevated the anti-LTD 4 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 LTD 4 with both activities at micromolar range. Radioligand binding studies have confirmed that the new compounds, but not cyproheptadine for LTD 4, exert their action through competetive occupation of the receptors. One compound, (S)-2-benzyloxycarbonyl-amino-3-[4-(10,11-dihydro-5 H-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 (ICS 50 = 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.