N-heteroaryl-2-phenyl-3-(benzyloxy)piperidines: a novel class of potent orally active human NK1 antagonists.
The preparation of a series of N-heteroarylpiperidine ether-based human NK1 antagonists is described. Two of the compounds 3-[-(2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)- 2-phenylpiperidino}methyl]-1,2,4-triazole (11) and 5-[¿(2S,3S)-3-(((3,5-bis(trifluoromethyl)-phenyl)methyl)oxy)-2- phenylpiperidino}methyl]-3-oxo-1,2,4-triazolone (12)), in particular, are orally bioavailable and exhibited significant improvements in potency, both in vitro and in vivo, over the lead (carboxamidomethyl)piperidine ether 1. Rat liver microsome studies on a selected number of compounds from this series show the triazolone heterocycle to be considerably more stable than the others. Furthermore, both 11 and 12 have been profiled in a number of assays that may be predictive of the clinical utility of substance P antagonists.
Ladduwahetty
T
T
Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK.
Baker
R
R
Cascieri
M A
MA
Chambers
M S
MS
Haworth
K
K
Keown
L E
LE
MacIntyre
D E
DE
Metzger
J M
JM
Owen
S
S
Rycroft
W
W
Sadowski
S
S
Seward
E M
EM
Shepheard
S L
SL
Swain
C J
CJ
Tattersall
F D
FD
Watt
A P
AP
Williamson
D W
DW
Hargreaves
R J
RJ
D000818:Animals; D001682:Biological Availability; D004355:Drug Stability; D005289:Ferrets; D006168:Guinea Pigs; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008881:Migraine Disorders / Q000188:drug therapy; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D014839:Vomiting / Q000188:drug therapy
C100728:3-((3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpiperidino)methyl)-1,2,4-triazole; C100729:5-((3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpiperidino)methyl)-3-oxo-1,2,4-triazolone; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D014230:Triazoles