2. Academic Validation
  3. 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

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

  • J Med Chem. 2006 Aug 24;49(17):5093-109. doi: 10.1021/jm060279f.
Teodozyj Kolasa 1,  Mark A Matulenko,  Ahmed A Hakeem,  Meena V Patel,  Kathleen Mortell,  Pramila Bhatia,  Rodger Henry,  Masaki Nakane,  Gin C Hsieh,  Marc A Terranova,  Marie E Uchic,  Loan N Miller,  Renje Chang,  Diana L Donnelly-Roberts,  Marian T Namovic,  Peter R Hollingsworth,  Brenda Martino,  Odile El Kouhen,  Kennan C Marsh,  Jill M Wetter,  Robert B Moreland,  Jorge D Brioni,  Andrew O Stewart
Affiliations

Affiliation

  • 1 Neuroscience Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101, USA. teodozyj.kolasa@abbott.com
PMID: 16913699 DOI: 10.1021/jm060279f
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.

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