title: 1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction.
abstract: A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.
authors.affiliation: Neuroscience Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101, USA. teodozyj.kolasa@abbott.com
authors.forename: Teodozyj
authors.initials: T
authors.lastname: Kolasa
authors.forename: Mark A
authors.initials: MA
authors.lastname: Matulenko
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Hakeem
authors.forename: Meena V
authors.initials: MV
authors.lastname: Patel
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mortell
authors.forename: Pramila
authors.initials: P
authors.lastname: Bhatia
authors.forename: Rodger
authors.initials: R
authors.lastname: Henry
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: Marc A
authors.initials: MA
authors.lastname: Terranova
authors.forename: Marie E
authors.initials: ME
authors.lastname: Uchic
authors.forename: Loan N
authors.initials: LN
authors.lastname: Miller
authors.forename: Renje
authors.initials: R
authors.lastname: Chang
authors.forename: Diana L
authors.initials: DL
authors.lastname: Donnelly-Roberts
authors.forename: Marian T
authors.initials: MT
authors.lastname: Namovic
authors.forename: Peter R
authors.initials: PR
authors.lastname: Hollingsworth
authors.forename: Brenda
authors.initials: B
authors.lastname: Martino
authors.forename: Odile
authors.initials: O
authors.lastname: El Kouhen
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wetter
authors.forename: Robert B
authors.initials: RB
authors.lastname: Moreland
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007172:Erectile Dysfunction / Q000188:drug therapy*; D005289:Ferrets; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D050638:Receptors, Dopamine D4 / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; C477501:N-((4-(2-cyanophenyl)-1-piperazinyl)methyl)-3-methylbenzamide; D010091:Oximes; D010879:Piperazines; D050638:Receptors, Dopamine D4