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4-(Phenylsulfonyl)piperidines:  Novel, Selective, and Bioavailable 5-HT2A Receptor Antagonists

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journal contribution
posted on 20.12.2001 by Stephen R. Fletcher, Frank Burkamp, Peter Blurton, Susan K. F. Cheng, Robert Clarkson, Desmond O'Connor, Daniel Spinks, Matthew Tudge, Monique B. van Niel, Smita Patel, Kerry Chapman, Rose Marwood, Sara Shepheard, Graham Bentley, Gina P Cook, Linda J Bristow, Jose L. Castro, Peter H. Hutson, Angus M. MacLeod
On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identifed as high-affinity, selective 5-HT2A receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.