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

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).

• Authors: Douglas S Johnson, Chung Choi, Lorraine K Fay, David A Favor, Joseph T Repine, Andrew D White, Hyacinth C Akunne, Lawrence Fitzgerald, Kim Nicholls, Bradley J Snyder, Steven Z Whetzel, Liming Zhang, Kevin A Serpa
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 9 Pg. 2621-5 (May 01 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21353774 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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