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

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 to...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-01, Vol.45 (2), p.492-503
Main Authors: Fletcher, Stephen R, Burkamp, Frank, Blurton, Peter, Cheng, Susan K. F, Clarkson, Robert, O'Connor, Desmond, Spinks, Daniel, Tudge, Matthew, van Niel, Monique B, Patel, Smita, Chapman, Kerry, Marwood, Rose, Shepheard, Sara, Bentley, Graham, Cook, Gina P, Bristow, Linda J, Castro, Jose L, Hutson, Peter H, MacLeod, Angus M
Format: Article
Language:English
Subjects:
Biological and medical sciences
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Serotoninergic system
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm011030v