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.
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.
Kolasa
Teodozyj
T
Neuroscience Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101, USA. teodozyj.kolasa@abbott.com
Matulenko
Mark A
MA
Hakeem
Ahmed A
AA
Patel
Meena V
MV
Mortell
Kathleen
K
Bhatia
Pramila
P
Henry
Rodger
R
Nakane
Masaki
M
Hsieh
Gin C
GC
Terranova
Marc A
MA
Uchic
Marie E
ME
Miller
Loan N
LN
Chang
Renje
R
Donnelly-Roberts
Diana L
DL
Namovic
Marian T
MT
Hollingsworth
Peter R
PR
Martino
Brenda
B
El Kouhen
Odile
O
Marsh
Kennan C
KC
Wetter
Jill M
JM
Moreland
Robert B
RB
Brioni
Jorge D
JD
Stewart
Andrew O
AO
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
D001549:Benzamides; C477501:N-((4-(2-cyanophenyl)-1-piperazinyl)methyl)-3-methylbenzamide; D010091:Oximes; D010879:Piperazines; D050638:Receptors, Dopamine D4