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

S M Bromidge; S Dabbs; D T Davies; S Davies; D M Duckworth; I T Forbes; L M Gaster; P Ham; G E Jones; F D King; K R Mulholland; D V Saunders; P A Wyman; F E Blaney; S E Clarke; T P Blackburn; V Holland; G A Kennett; S Lightowler; D N Middlemiss; B Trail; G J Riley; M D Wood

doi:10.1021/jm990388c

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

J Med Chem. 2000 Mar 23;43(6):1123-34. doi: 10.1021/jm990388c.

Affiliation

¹ SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Steve_Bromidge-1@sbphrd.com

PMID: 10737744
DOI: 10.1021/jm990388c

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.

MeSH terms

Administration, Oral
Animals
Anti-Anxiety Agents / chemical synthesis*
Anti-Anxiety Agents / chemistry
Anti-Anxiety Agents / metabolism
Anti-Anxiety Agents / pharmacology
Antidepressive Agents / chemical synthesis*
Antidepressive Agents / chemistry
Antidepressive Agents / metabolism
Antidepressive Agents / pharmacology
Cell Line
Humans
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / metabolism
Indoles / pharmacology
Models, Molecular
Motor Activity / drug effects
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / metabolism
Pyridines / pharmacology
Radioligand Assay
Rats
Receptor, Serotonin, 5-HT2A
Receptor, Serotonin, 5-HT2B
Receptor, Serotonin, 5-HT2C
Receptors, Serotonin / metabolism*
Serotonin Receptor Agonists / chemical synthesis*
Serotonin Receptor Agonists / chemistry
Serotonin Receptor Agonists / metabolism
Serotonin Receptor Agonists / pharmacology
Structure-Activity Relationship

Substances

Anti-Anxiety Agents
Antidepressive Agents
Indoles
Pyridines
Receptor, Serotonin, 5-HT2A
Receptor, Serotonin, 5-HT2B
Receptor, Serotonin, 5-HT2C
Receptors, Serotonin
Serotonin Receptor Agonists
SB 228357
SB 243213