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

Abstract

Abstract The synthesis and the histamine H 1 antagonism of four racemates of 1‐[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 mg/kg 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 mg/kg of levocabastine, whereas a dose of 2.5 mg/kg, failed to protect guinea pigs from dyspnea induced by serotonin or acetylcholine aerosols.