title: Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent.
abstract: The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5-HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Steve_Bromidge-1@sbphrd.com
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: S
authors.initials: S
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: L M
authors.initials: LM
authors.lastname: Gaster
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: K R
authors.initials: KR
authors.lastname: Mulholland
authors.forename: D V
authors.initials: DV
authors.lastname: Saunders
authors.forename: P A
authors.initials: PA
authors.lastname: Wyman
authors.forename: F E
authors.initials: FE
authors.lastname: Blaney
authors.forename: S E
authors.initials: SE
authors.lastname: Clarke
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: S
authors.initials: S
authors.lastname: Lightowler
authors.forename: D N
authors.initials: DN
authors.lastname: Middlemiss
authors.forename: B
authors.initials: B
authors.lastname: Trail
authors.forename: G J
authors.initials: GJ
authors.lastname: Riley
authors.forename: M D
authors.initials: MD
authors.lastname: Wood
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D007211:Indoles; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C118947:SB 228357; C406343:SB 243213