title: Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction.
abstract: A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.
authors.affiliation: Department of Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064-6123, USA. marlon.d.cowart@abbott.com
authors.forename: Marlon
authors.initials: M
authors.lastname: Cowart
authors.forename: Steven P
authors.initials: SP
authors.lastname: Latshaw
authors.forename: Pramila
authors.initials: P
authors.lastname: Bhatia
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Daanen
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rohde
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Nelson
authors.forename: Meena
authors.initials: M
authors.lastname: Patel
authors.forename: Teodozyi
authors.initials: T
authors.lastname: Kolasa
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
authors.forename: Marie E
authors.initials: ME
authors.lastname: Uchic
authors.forename: Loan N
authors.initials: LN
authors.lastname: Miller
authors.forename: Marc A
authors.initials: MA
authors.lastname: Terranova
authors.forename: Renjie
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 R
authors.initials: BR
authors.lastname: Martino
authors.forename: James J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
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; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D007172:Erectile Dysfunction / Q000188:drug therapy*; D005289:Ferrets; D006801:Humans; D008297:Male; D010410:Penile Erection / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050638:Receptors, Dopamine D4; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced
chemical_list: C487766:ABT724; D001562:Benzimidazoles; C493599:DRD4 protein, human; C493601:Drd4 protein, rat; D010879:Piperazines; D011725:Pyridines; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4