| Autor: |
Ladduwahetty, T., Baker, R., Cascieri, M. A., Chambers, M. S., Haworth, K., Keown, L. E., MacIntyre, D. E., Metzger, J. M., Owen, S., Rycroft, W., Sadowski, S., Seward, E. M., Shepheard, S. L., Swain, C. J., Tattersall, F. D., Watt, A. P., Williamson, D. W., Hargreaves, R. J. |
| Zdroj: |
Journal of Medicinal Chemistry; July 19, 1996, Vol. 39 Issue: 15 p2907-2914, 8p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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