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

Affiliation

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.

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