1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: potent, selective, and orally efficacious norepinephrine reuptake inhibitors. Journal of medicinal chemistry [J Med Chem] Journal article | | Title | 1- or 3-(3-Amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones: potent, selective, and orally efficacious norepinephrine reuptake inhibitors. | | Author(s) | Zhang P, Terefenko EA, Bray J, Deecher D, Fensome A, Harrison J, Kim C, Koury E, Mark L, McComas CC, Mugford CA, Trybulski EJ, Vu AT, Whiteside GT, Mahaney PE | | Institution | Chemical Sciences, Wyeth Research, S-2250B, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. Zhangp@wyeth.com | | Source | J Med Chem 2009 Sep 24; 52(18):5703-11. | | MeSH | Administration, Oral
Animals
Behavior, Animal
Benzimidazoles
Biological Transport
Dopamine Plasma Membrane Transport Proteins
Female
Humans
Hyperalgesia
Male
Neurotransmitter Uptake Inhibitors
Norepinephrine
Norepinephrine Plasma Membrane Transport Proteins
Propanolamines
Rats
Rats, Sprague-Dawley
Serotonin Plasma Membrane Transport Proteins
Spinal Nerves
Structure-Activity Relationship
Substrate Specificity
| | Abstract | Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 19722525 |
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