Levocabastine (R 50547): The prototype of a chemical series of compounds with specific H₁‐antihistaminic activity

Abstract

Stokbroekx R.A., M.G.M. Luyckx, J.J.M. Willerns, M. Janssen, J.O.M.M. Bracke, R.L.P. Joosen, and J.P. Van Wauwe: Levocabastine (R 50547): The prototype of a chemical series of compounds with specific HI-antihistaminic activity. Drug Dev. Res. 8:87-93, 1986.The synthesis and the histamine HI antagonism of four racemates of l-[cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid, termed R 48756, R 49389, R 49429, and R 49549, are described. R48756 (cabastine) was found to be the most potent compound, with oral ED50 values of 0.002-0.003 mglkg in both the histamineinduced lethality test (guinea pigs) and the compound 48/80 assay (rats). Upon resolution of cabastine into its two optical isomers, levocabastine (R 50547) after oral administration in guinea pigs was about four times (1 hr) to 90 times (24 hr) more potent than dextrocabastine (R 50554). Protection from dyspnea, induced by histamine aerosols, was obtained with 0.005 mglkg of levocabastine, whereas a dose of 2.5 mglkg, failed to protect guinea pigs from dyspnea induced by serotonin or acetylcholine aerosols.

Antiedematogenic Evaluation ofCopaifera langsdorffiiLeaves Hydroethanolic Extract and Its Major Compounds

“…Therefore, the results showed that Cop inhibit dextran-induced plasma extravasation. On the other hand, a selective antihistaminic that lacks antiserotonin activity failed to block dextran-induced vascular permeability changes, ruling out a participating role for histamine in this type of inflammatory reaction [ 26 ]. Therefore, the weak activity observed for Cop on carrageenan-induced paw oedema at the 1 h could be attributed to the participation of histamine in carrageenan-induced paw oedema.…”

A structure–activity relationship study of compounds with antihistamine activity

“…Affiliation of particular compounds with the groups of biological activity was established based on literature data (Van der Brook et al, 1948;Chinn and Smith, 1955;Marshall, 1955;Loew et al, 1967;Witiak et al, 1971;Brimblecombe et al, 1975a, b;Ebnöther and Weber, 1976;Martin and Romer, 1978;Bradshaw et al, 1979;Uzan et al, 1979;Daly et al, 1980;Van Wauwe et al, 1981;Wauquier and Niemegeers, 1981;Barnett et al, 1984;Takabatake et al, 1985;Stokbroekx et al, 1986;De Vos et al, 1987;Juhlin et al, 1987;Grant et al, 1990;Tasaka et al, 1990;Piwinski et al, 1991;Canonica et al, 1992;La Blaye et al, 1992;Jannssens and Howarth, 1993;Jannssens, 1993;Danysz, 1994;Walczynski et al, 1999aWalczynski et al, c, 2000Kemmritz, 2003;Swiader et al, 2004). In the qualitative analysis, lipophilicity of the examined compounds (log P) was additionally used.…”

“…The following group codes were assigned to them a priori: I1 (for compounds 34-39, first generation drugs; Van der Brook et al, 1948;Chinn and Smith, 1955;Marshall, 1955;Loew et al, 1967;Witiak et al, 1971;Ebnöther and Weber, 1976;Martin and Romer, 1978;Uzan et al, 1979;Stokbroekx et al, 1986;Grant et al, 1990;Tasaka et al, 1990;Le Blaye et al, 1992;Danysz, 1994;Kemmritz, 2003;Swiader et al, 2004); I2 (for compounds 40-42, second generation drugs; Van Wauwe et al, 1981;Wauquier and Niemegeers, 1981;Barnett et al, 1984;De Vos et al, 1987;Juhlin et al, 1987;Piwinski et al, 1991;Canonica et al, 1992;Jannssens and Howarth, 1993;Jannssens, 1993); II (for compounds 43-45, with anti-H 2 activity; Brimblecombe et al, 1975a, b;Bradshaw et al, 1979;Daly et al, 1980;Takabatake et al, 1985); and A [thiazolederivative compounds 46-49 with H 1 agonistic activity (Walczynski et al, 1999a)].…”

Absence of central effects with levocabastine eye drops

“…Levocabastine is a potent, specific and fastacting histamine-Hl-receptor antagonist (1,10,11). In clinical studies using topical administration (eye drops and nasal spray), its efficacy in the treatment of allergic conjunctivitis and allergic rhinitis has been established (2,9).…”