Document Report Card

ID: ALA1129245

Journal: J Med Chem

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

Authors: Ladduwahetty T, Baker R, Cascieri MA, Chambers MS, Haworth K, Keown LE, MacIntyre DE, Metzger JM, Owen S, Rycroft W, Sadowski S, Seward EM, Shepheard SL, Swain CJ, Tattersall FD, Watt AP, Williamson DW, Hargreaves RJ.

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.

CiteXplore: 8709125

DOI: 10.1021/jm9506534