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3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as High Affinity, Selective, and Orally Bioavailable h5-HT 2A Receptor Antagonists

2001; American Chemical Society; Volume: 44; Issue: 10 Linguagem: Inglês

10.1021/jm0004998

1520-4804

Michael Rowley, David J. Hallett, Simon Goodacre, Christopher R. Moyes, James Crawforth, T. J. SPAREY, Smita S. Patel, Rose Marwood, Shil Patel, Steven R. Thomas, Laure Hitzel, Desmond O’Connor, Nicola Szeto, José L. Castro, Peter H. Hutson, Angus M. MacLeod,

Receptor Mechanisms and Signaling

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.