Design and synthesis of novel tricyclic benzoxazines as potent 5-HT(1A/B/D) receptor antagonists leading to the discovery of 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045)

J Med Chem. 2010 Aug 12;53(15):5827-43. doi: 10.1021/jm100482n.

Abstract

Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / chemical synthesis*
  • Anti-Anxiety Agents / pharmacokinetics
  • Anti-Anxiety Agents / pharmacology
  • Antidepressive Agents / chemical synthesis*
  • Antidepressive Agents / pharmacokinetics
  • Antidepressive Agents / pharmacology
  • Benzoxazines / chemical synthesis*
  • Benzoxazines / pharmacokinetics
  • Benzoxazines / pharmacology
  • Callithrix
  • Cell Line
  • Cerebral Cortex / metabolism
  • Cricetinae
  • Cricetulus
  • Cytochrome P-450 Enzyme System / metabolism
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Male
  • Microsomes, Liver / metabolism
  • Protein Binding
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin 5-HT1 Receptor Antagonists*
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • 6-(2-(4-(2-methyl-5-quinolinyl)-1-piperazinyl)ethyl)-4H-imidazo(5,1-c)(1,4)benzoxazine-3-carboxamide
  • Anti-Anxiety Agents
  • Antidepressive Agents
  • Benzoxazines
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Plasma Membrane Transport Proteins
  • Cytochrome P-450 Enzyme System