| Autor: |
Rowley, M., Hallett, D. J., Goodacre, S., Moyes, C., Crawforth, J., Sparey, T. J., Patel, Sm., Marwood, R., Patel, Sh., Thomas, S., Hitzel, L., O'Connor, D., Szeto, N., Castro, J. L., Hutson, P. H., MacLeod, A. M. |
| Zdroj: |
Journal of Medicinal Chemistry; May 2001, Vol. 44 Issue: 10 p1603-1614, 12p |
| Abstrakt: |
The development of very high affinity, selective, and bioavailable h5-HT2A receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT2A receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pKa of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the 6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT2A receptors, with bioavailability of 80% and half-life of 12 h in rats. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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