title: 4-(Phenylsulfonyl)piperidines: novel, selective, and bioavailable 5-HT(2A) receptor antagonists.
abstract: On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) 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.
authors.affiliation: Merck Sharp and Dohme, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. stephen_fletcher@merck.com
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Fletcher
authors.forename: Frank
authors.initials: F
authors.lastname: Burkamp
authors.forename: Peter
authors.initials: P
authors.lastname: Blurton
authors.forename: Susan K F
authors.initials: SK
authors.lastname: Cheng
authors.forename: Robert
authors.initials: R
authors.lastname: Clarkson
authors.forename: Desmond
authors.initials: D
authors.lastname: O'Connor
authors.forename: Daniel
authors.initials: D
authors.lastname: Spinks
authors.forename: Matthew
authors.initials: M
authors.lastname: Tudge
authors.forename: Monique B
authors.initials: MB
authors.lastname: van Niel
authors.forename: Smita
authors.initials: S
authors.lastname: Patel
authors.forename: Kerry
authors.initials: K
authors.lastname: Chapman
authors.forename: Rose
authors.initials: R
authors.lastname: Marwood
authors.forename: Sara
authors.initials: S
authors.lastname: Shepheard
authors.forename: Graham
authors.initials: G
authors.lastname: Bentley
authors.forename: Gina P
authors.initials: GP
authors.lastname: Cook
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bristow
authors.forename: Jose L
authors.initials: JL
authors.lastname: Castro
authors.forename: Peter H
authors.initials: PH
authors.lastname: Hutson
authors.forename: Angus M
authors.initials: AM
authors.lastname: MacLeod
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D027682:Cation Transport Proteins; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins; D004353:Drug Evaluation, Preclinical; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005289:Ferrets; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: C446060:1-(4-fluorophenyl)-2-(4-(phenylsulfonyl)-1-piperidinyl)ethanone; C446059:4-((1-(2-(2,4-difluorophenyl)ethyl)-4-piperidinyl)sulfonyl)benzamide; C446058:4-((1-(2-(2,4-difluorophenyl)ethyl)-4-piperidinyl)sulfonyl)benzonitrile; D001549:Benzamides; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D009570:Nitriles; D010880:Piperidines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; D013450:Sulfones; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG