3-(4-fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT2A receptor antagonist

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 S-position of the piperidine it w as not necessary to further substitute the piperidine in order to obtain go od binding at h5-HT2A receptors. This meant the compounds no longer had hig h affinity at the IKr potassium channel, an issue with previous series of 2 -aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailab ility in this series by reduction of the pK(a) of the basic nitrogen, by ad ding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidi n-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound ident ified oxidation at the B-position of the indole as a major route in vitro a nd in vivo in rats. Blocking this position with a fluorine atom led to 6-fl uoro-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 ha lf-life of 12 h in rats.