Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists
Chen, M.H.; Chung, F.Z.; Roth, B.D.; Kuo, B.S.; Atherton, J.; Lee, H.T.
Zhongguo Yao Li Xue Bao 20(3): 283-288
1999
ISSN/ISBN: 0253-9756 PMID: 10452109 Document Number: 509678
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 (IC50 = 5.9, 6.2, and 11 nmolcntdotL-1, respectively) than the monosubstituted ring compound 1e (IC50 = 17 nmolcntdotL-1). 4-Phenyl (1b) and 4-phenylsulfonylmethyl (1c) compounds were more active than the 4-fluorobenzyl compound (1d). All antagonists were found to be orally absorbable, the T1/2 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 (IC50 = 5.9 nmolcntdotL-1) and the best AUC (2081 mugcntdothcntdotL-1).