Discovery of PF-00217830: aryl piperazine napthyridinones as D2 partial agonists for schizophrenia and bipolar disorder

Bioorg Med Chem Lett. 2011 May 1;21(9):2621-5. doi: 10.1016/j.bmcl.2011.01.059. Epub 2011 Jan 22.

Abstract

The synthesis and structure-activity relationship (SAR) of a novel series of aryl piperazine napthyridinone D(2) partial agonists is described. Our goal was to optimize the affinities for the D(2), 5-HT(2A) and 5-HT(1A) receptors, such that the D(2)/5-HT(2A) ratio was greater than 5 to ensure maximal occupancy of these receptors when the D(2) occupancy reached efficacious levels. This strategy led to identification of PF-00217830 (2) with robust inhibition of sLMA (MED=0.3mg/kg) and DOI-induced head twitches in rats (31% and 78% at 0.3 and 1mg/kg) with no catalepsy observed at the highest dose tested (10 mg/kg).

MeSH terms

  • Animals
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / pharmacology*
  • Bipolar Disorder / drug therapy
  • Drug Discovery
  • Haplorhini
  • Male
  • Molecular Structure
  • Naphthyridines / chemistry*
  • Naphthyridines / pharmacokinetics
  • Naphthyridines / pharmacology*
  • Piperazine
  • Piperazines / chemistry*
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Rats
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D2 / chemistry
  • Schizophrenia / drug therapy
  • Structure-Activity Relationship

Substances

  • Antipsychotic Agents
  • Naphthyridines
  • PF 00217830
  • Piperazines
  • Receptors, Dopamine D2
  • Piperazine