Discovery and SAR of potent, orally available and brain-penetrable 5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen- and 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen derivatives as neuropeptide Y Y5 receptor antagonists

Bioorg Med Chem Lett. 2004 May 17;14(10):2451-7. doi: 10.1016/j.bmcl.2004.03.014.

Abstract

Combination of structural elements from a potent Y5 antagonist (2) with thiazole fragments that exhibit weak Y5 affinities followed by lead optimisation led to the discovery of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino derivatives. Both classes of compounds are capable of delivering potent and selective orally and centrally bioavailable NPY Y5 receptor antagonists.

MeSH terms

  • Administration, Oral
  • Animals
  • Azulenes
  • Biological Availability
  • Blood
  • Blood-Brain Barrier
  • Cycloheptanes / chemical synthesis*
  • Cycloheptanes / pharmacokinetics*
  • Cycloheptanes / pharmacology
  • Heterocyclic Compounds, 3-Ring / chemical synthesis
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / pharmacokinetics
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Hypothalamus
  • Inhibitory Concentration 50
  • Rats
  • Receptors, Neuropeptide Y / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Azulenes
  • Cycloheptanes
  • Heterocyclic Compounds, 3-Ring
  • Heterocyclic Compounds, 4 or More Rings
  • Receptors, Neuropeptide Y
  • neuropeptide Y5 receptor
  • azulene