title: 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=0.3mg/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).
authors.affiliation: Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA. doug.johnson@pfizer.com
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Chung
authors.initials: C
authors.lastname: Choi
authors.forename: Lorraine K
authors.initials: LK
authors.lastname: Fay
authors.forename: David A
authors.initials: DA
authors.lastname: Favor
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Repine
authors.forename: Andrew D
authors.initials: AD
authors.lastname: White
authors.forename: Hyacinth C
authors.initials: HC
authors.lastname: Akunne
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fitzgerald
authors.forename: Kim
authors.initials: K
authors.lastname: Nicholls
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Snyder
authors.forename: Steven Z
authors.initials: SZ
authors.lastname: Whetzel
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Serpa
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy; D055808:Drug Discovery; D000882:Haplorhini; D008297:Male; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000737:chemistry; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D009287:Naphthyridines; C560205:PF 00217830; D010879:Piperazines; D017448:Receptors, Dopamine D2; D000077489:Piperazine