Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists.
OBJECTIVE
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 nmol.L-1, respectively) than the monosubstituted ring compound 1e (IC50 = 17 nmol.L-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).


CONCLUSIONS
Compound 1b had the best binding activity (IC50 = 5.9 nmol.L-1) and the best AUC (2081 micrograms.h.L-1).
Chen
M H
MH
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Chung
F Z
FZ
Roth
B D
BD
Kuo
B S
BS
Atherton
J
J
Lee
H T
HT
D000818:Animals; D019540:Area Under Curve; D007408:Intestinal Absorption; D008297:Male; D015287:Neurokinin B / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010880:Piperidines / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010880:Piperidines; D018042:Receptors, Neurokinin-3; D015287:Neurokinin B; C091554:SR 142801