Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists

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AIM: To develop nonpeptide tachykinin NK3 antagonists. METHODS: Five tachykinin NK3 antagonists were synthesized. Receptor binding assay and oral absorption study were made. RESULTS: The 4,4 disubstituted piperidine compounds (1b, 1c, and 1d) showed stronger activities (IC 50 = 5 9, 6 2, and 11 nmol·L -1 , respectively) than the monosubstituted ring compound 1e (IC 50 =17 nmol·L -1 ). 4 Phenyl (1b) and 4 phenylsulfonylmethyl (1c) com￣pounds were more active than the 4 fluorobenzyl compound (1d). All antagonists were found to be orally absorbable, the T 1/2 of 1b (6 4 h) was more than three fold longer than that of 1a (1 9 h). CONCLUSION: Compound 1b had the best binding activity (IC 50 = 5 9 nmol·L -1 ) and the best AUC (2081 μg·h·L -1 ).