title: 3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT(2A) receptor antagonists.
abstract: The development of very high affinity, selective, and bioavailable h5-HT(2A) 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 3-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT(2A) receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pK(a) of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the 6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT(2A) receptors, with bioavailability of 80% and half-life of 12 h in rats.
authors.affiliation: Merck Sharp and Dohme, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. michael_rowley@merck.com
authors.forename: M
authors.initials: M
authors.lastname: Rowley
authors.forename: D J
authors.initials: DJ
authors.lastname: Hallett
authors.forename: S
authors.initials: S
authors.lastname: Goodacre
authors.forename: C
authors.initials: C
authors.lastname: Moyes
authors.forename: J
authors.initials: J
authors.lastname: Crawforth
authors.forename: T J
authors.initials: TJ
authors.lastname: Sparey
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: R
authors.initials: R
authors.lastname: Marwood
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: S
authors.initials: S
authors.lastname: Thomas
authors.forename: L
authors.initials: L
authors.lastname: Hitzel
authors.forename: D
authors.initials: D
authors.lastname: O'Connor
authors.forename: N
authors.initials: N
authors.lastname: Szeto
authors.forename: J L
authors.initials: JL
authors.lastname: Castro
authors.forename: P H
authors.initials: PH
authors.lastname: Hutson
authors.forename: A M
authors.initials: AM
authors.lastname: MacLeod
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D004285:Dogs; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C427231:3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole; C427230:6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole; D007211:Indoles; D010880:Piperidines; D015221:Potassium Channels; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists