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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| Veröffentlicht in: | Journal of medicinal chemistry 2002-01, Vol.45 (2), p.492-503 |
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| container_end_page | 503 |
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| container_issue | 2 |
| container_start_page | 492 |
| container_title | Journal of medicinal chemistry |
| container_volume | 45 |
| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1021/jm011030v |
| format | Article |
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Chem</addtitle><description>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.</description><subject>Biological and medical sciences</subject><subject>Medical sciences</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. 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| source | American Chemical Society Journals |
| subjects | Biological and medical sciences Medical sciences Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Serotoninergic system |
| title | 4-(Phenylsulfonyl)piperidines: Novel, Selective, and Bioavailable 5-HT2A Receptor Antagonists |
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