title: Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines.
abstract: The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, England.
authors.forename: S M
authors.initials: SM
authors.lastname: Bromidge
authors.forename: S
authors.initials: S
authors.lastname: Dabbs
authors.forename: D T
authors.initials: DT
authors.lastname: Davies
authors.forename: D M
authors.initials: DM
authors.lastname: Duckworth
authors.forename: I T
authors.initials: IT
authors.lastname: Forbes
authors.forename: P
authors.initials: P
authors.lastname: Ham
authors.forename: G E
authors.initials: GE
authors.lastname: Jones
authors.forename: F D
authors.initials: FD
authors.lastname: King
authors.forename: D V
authors.initials: DV
authors.lastname: Saunders
authors.forename: S
authors.initials: S
authors.lastname: Starr
authors.forename: K M
authors.initials: KM
authors.lastname: Thewlis
authors.forename: P A
authors.initials: PA
authors.lastname: Wyman
authors.forename: F E
authors.initials: FE
authors.lastname: Blaney
authors.forename: C B
authors.initials: CB
authors.lastname: Naylor
authors.forename: F
authors.initials: F
authors.lastname: Bailey
authors.forename: T P
authors.initials: TP
authors.lastname: Blackburn
authors.forename: V
authors.initials: V
authors.lastname: Holland
authors.forename: G A
authors.initials: GA
authors.lastname: Kennett
authors.forename: G J
authors.initials: GJ
authors.lastname: Riley
authors.forename: M D
authors.initials: MD
authors.lastname: Wood
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003220:Conflict, Psychological; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012919:Social Behavior; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D007211:Indoles; D011725:Pyridines; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; C112099:SB 221284; D012702:Serotonin Antagonists