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

The synthesis and structure-activity relationship (SAR) of a novel series of aryl piperazine napthyridinone D sub(2 partial agonists is described. Our goal was to optimize the affinities for the D) sub(2), 5-HT sub(2A and 5-HT) sub(1)A receptors, such that the D sub(2/5-HT) sub(2)A ratio was greater than 5 to ensure maximal occupancy of these receptors when the D sub(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).)