N-heteroaryl-2-phenyl-3-(benzyloxy)piperidines: a novel class of potent orally active human NK1 antagonists

  • J Med Chem. 1996 Jul 19;39(15):2907-14. doi: 10.1021/jm9506534.
T Ladduwahetty  1 ,  R Baker ,  M A Cascieri ,  M S Chambers ,  K Haworth ,  L E Keown ,  D E MacIntyre ,  J M Metzger ,  S Owen ,  W Rycroft ,  S Sadowski ,  E M Seward ,  S L Shepheard ,  C J Swain ,  F D Tattersall ,  A P Watt ,  D W Williamson ,  R J Hargreaves
Affiliations
  • 1. Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK.
PMID: 8709125 DOI: 10.1021/jm9506534
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.