Selective 5-HT2C receptor agonists: Design and synthesis of pyridazine-fused azepines

Bioorg Med Chem Lett. 2016 Aug 15;26(16):4117-21. doi: 10.1016/j.bmcl.2016.06.060. Epub 2016 Jun 23.

Abstract

Heterocycle-fused azepines are discussed as potent 5-HT2C receptor agonists with excellent selectivity over 5-HT2B agonism. Synthesis and structure activity relationships are outlined for a series of bicyclic pyridazino[3,4-d]azepines. By comparison with earlier published work, in vitro assays predict a high probability for achieving CNS penetration for a potent and selective compound 15a, a pre-requisite to achieve in vivo efficacy.

Keywords: 5-HT(2C) receptor agonists; CNS penetration; Obesity; Pyridazino[3,4-d]azepines; Urinary incontinence.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Azepines / chemical synthesis
  • Azepines / chemistry*
  • Azepines / metabolism
  • Dogs
  • Drug Design*
  • Humans
  • Madin Darby Canine Kidney Cells
  • Protein Binding
  • Pyridazines / chemistry*
  • Receptor, Serotonin, 5-HT2B / chemistry
  • Receptor, Serotonin, 5-HT2B / metabolism
  • Receptor, Serotonin, 5-HT2C / chemistry
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin 5-HT2 Receptor Agonists / chemical synthesis*
  • Serotonin 5-HT2 Receptor Agonists / chemistry
  • Serotonin 5-HT2 Receptor Agonists / metabolism
  • Structure-Activity Relationship

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Azepines
  • Pyridazines
  • Receptor, Serotonin, 5-HT2B
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists
  • pyridazine