| Autor: |
Ladduwahetty T; Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK., 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 |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 1996 Jul 19; Vol. 39 (15), pp. 2907-14. |
| DOI: |
10.1021/jm9506534 |
| 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: |
MEDLINE |
| Externí odkaz: |
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