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.
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.
Cowart
Marlon
M
Department of Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064-6123, USA. marlon.d.cowart@abbott.com
Latshaw
Steven P
SP
Bhatia
Pramila
P
Daanen
Jerome F
JF
Rohde
Jeffrey
J
Nelson
Sherry L
SL
Patel
Meena
M
Kolasa
Teodozyi
T
Nakane
Masaki
M
Uchic
Marie E
ME
Miller
Loan N
LN
Terranova
Marc A
MA
Chang
Renjie
R
Donnelly-Roberts
Diana L
DL
Namovic
Marian T
MT
Hollingsworth
Peter R
PR
Martino
Brenda R
BR
Lynch
James J
JJ
Sullivan
James P
JP
Hsieh
Gin C
GC
Moreland
Robert B
RB
Brioni
Jorge D
JD
Stewart
Andrew O
AO
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
C487766:ABT724; D001562:Benzimidazoles; C493599:DRD4 protein, human; C493601:Drd4 protein, rat; D010879:Piperazines; D011725:Pyridines; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4