Discovery of Lu AA33810: a highly selective and potent NPY5 antagonist with in vivo efficacy in a model of mood disorder

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5436-41. doi: 10.1016/j.bmcl.2011.06.124. Epub 2011 Jul 2.

Abstract

The structure-activity relationship of a series of tricyclic-sulfonamide compounds 11-32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6-dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). In addition, ip administration of Lu AA33810 (10 mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress.

MeSH terms

  • Animals
  • Benzothiepins / chemical synthesis
  • Benzothiepins / chemistry
  • Benzothiepins / pharmacology*
  • Biological Availability
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Mice
  • Molecular Structure
  • Mood Disorders / drug therapy*
  • Mood Disorders / metabolism
  • Rats
  • Receptors, Neuropeptide Y / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Benzothiepins
  • N-((4-((4,5-dihydro(1)benzothiepino(5,4-d)thiazol-2-yl)amino)cyclohexyl)methyl)methanesulfonamide
  • Receptors, Neuropeptide Y
  • Sulfonamides
  • neuropeptide Y5 receptor