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 effic...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-08, Vol.49 (17), p.5093-5109
Main Authors: Kolasa, Teodozyj, Matulenko, Mark A, Hakeem, Ahmed A, Patel, Meena V, Mortell, Kathleen, Bhatia, Pramila, Henry, Rodger, Nakane, Masaki, Hsieh, Gin C, Terranova, Marc A, Uchic, Marie E, Miller, Loan N, Chang, Renje, Donnelly-Roberts, Diana L, Namovic, Marian T, Hollingsworth, Peter R, Martino, Brenda, El Kouhen, Odile, Marsh, Kennan C, Wetter, Jill M, Moreland, Robert B, Brioni, Jorge D, Stewart, Andrew O
Format: Article
Language:English
Subjects:
Animals
Benzamides - chemistry
Benzamides - pharmacology
Binding Sites
Biological and medical sciences
Cell Line
Crystallography, X-Ray
Disease Models, Animal
Drug Evaluation, Preclinical
Erectile Dysfunction - drug therapy
Ferrets
Genital system. Reproduction
Humans
Male
Medical sciences
Models, Molecular
Molecular Structure
Oximes - chemical synthesis
Oximes - chemistry
Oximes - pharmacology
Pharmacology. Drug treatments
Piperazines - chemical synthesis
Piperazines - chemistry
Piperazines - pharmacology
Rats
Rats, Wistar
Receptors, Dopamine D4 - agonists
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060279f