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

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.
Douglas S Johnson 1,  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
Affiliations

Affiliation

  • 1 Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA. [email protected]
PMID: 21353774 DOI: 10.1016/j.bmcl.2011.01.059
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).

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