title: N-heteroaryl-2-phenyl-3-(benzyloxy)piperidines: a novel class of potent orally active human NK1 antagonists.
abstract: 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.
authors.affiliation: Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK.
authors.forename: T
authors.initials: T
authors.lastname: Ladduwahetty
authors.forename: R
authors.initials: R
authors.lastname: Baker
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: M S
authors.initials: MS
authors.lastname: Chambers
authors.forename: K
authors.initials: K
authors.lastname: Haworth
authors.forename: L E
authors.initials: LE
authors.lastname: Keown
authors.forename: D E
authors.initials: DE
authors.lastname: MacIntyre
authors.forename: J M
authors.initials: JM
authors.lastname: Metzger
authors.forename: S
authors.initials: S
authors.lastname: Owen
authors.forename: W
authors.initials: W
authors.lastname: Rycroft
authors.forename: S
authors.initials: S
authors.lastname: Sadowski
authors.forename: E M
authors.initials: EM
authors.lastname: Seward
authors.forename: S L
authors.initials: SL
authors.lastname: Shepheard
authors.forename: C J
authors.initials: CJ
authors.lastname: Swain
authors.forename: F D
authors.initials: FD
authors.lastname: Tattersall
authors.forename: A P
authors.initials: AP
authors.lastname: Watt
authors.forename: D W
authors.initials: DW
authors.lastname: Williamson
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
mesh_terms: 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
chemical_list: 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