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

Article Details

Citation

Copy to clipboard

Johnson DS, Choi C, Fay LK, Favor DA, Repine JT, White AD, Akunne HC, Fitzgerald L, Nicholls K, Snyder BJ, Whetzel SZ, Zhang L, Serpa KA

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.

PubMed ID

21353774 [ View in PubMed

]

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).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Aripiprazole	5-hydroxytryptamine receptor 1A	Ki (nM)	10.3	N/A	N/A	Details
Aripiprazole	5-hydroxytryptamine receptor 2A	Ki (nM)	9.6	N/A	N/A	Details
Aripiprazole	Dopamine D2 receptor	Ki (nM)	1.8	N/A	N/A	Details