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 = 0.3 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).