Discovery of PF-00217830: Aryl piperazine napthyridinones as D 2 partial agonists for schizophrenia and bipolar disorder

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 occu...

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Published inBioorganic & medicinal chemistry letters Vol. 21; no. 9; pp. 2621 - 2625
Main Authors Johnson, Douglas S., Choi, Chung, Fay, Lorraine K., Favor, David A., Repine, Joseph T., White, Andrew D., Akunne, Hyacinth C., Fitzgerald, Lawrence, Nicholls, Kim, Snyder, Bradley J., Whetzel, Steven Z., Zhang, Liming, Serpa, Kevin A.
Format Journal Article
LanguageEnglish
Published Elsevier Ltd 01.05.2011
Subjects
D 2 partial agonist
Napthyridinone
PF-00217830
Schizophrenia
D 2 partial agonist
Napthyridinone
Schizophrenia
PF-00217830
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Summary: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 = 0.3 mg/kg) and DOI-induced head twitches in rats (31% and 78% at 0.3 and 1 mg/kg) with no catalepsy observed at the highest dose tested (10 mg/kg).
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.01.059