Research article summary (published 22 Sep 2009):

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.

Full 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.

Author information

Author/s: Zhang, Puwen (P); Terefenko, Eugene A (EA); Bray, Jenifer (J); Deecher, Darlene (D); Fensome, Andrew (A); Harrison, Jim (J); Kim, Callain (C); Koury, Elizabeth (E); Mark, Lilly (L); McComas, Casey C (CC); Mugford, Cheryl A (CA); Trybulski, Eugene J (EJ); Vu, An T (AT); Whiteside, Garth T (GT); Mahaney, Paige E (PE);

Affiliation: Chemical Sciences, Wyeth Research, S-2250B, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. Zhangp(-atsign-)wyeth.com

Journal and publication information

Publication Type: Journal Article

Journal: Journal of medicinal chemistry (J Med Chem), published in United States. (Language: eng)

Reference: 2009-Sep; vol 52 (issue 18) : pp 5703-11

Dates: Created 2009/09/17; Completed 2009/10/14;

PMID: 19722525, status: MEDLINE (last retrieval date: 10/14/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Administration, Oral Animals Behavior, Animal - drug effects Benzimidazoles - administration & dosage; chemistry; pharmacokinetics; pharmacology Biological Transport - drug effects Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors Female Humans Hyperalgesia - physiopathology Male

Neurotransmitter Uptake Inhibitors - administration & dosage; chemistry; pharmacokinetics; pharmacology Norepinephrine - metabolism Norepinephrine Plasma Membrane Transport Proteins - antagonists & inhibitors Propanolamines - chemistry Rats Rats, Sprague-Dawley Serotonin Plasma Membrane Transport Proteins - metabolism Spinal Nerves - drug effects; physiology Structure-Activity Relationship Substrate Specificity

Associated Chemicals: Benzimidazoles (0) ; Dopamine Plasma Membrane Transport Proteins (0) ; Neurotransmitter Uptake Inhibitors (0) ; Norepinephrine Plasma Membrane Transport Proteins (0) ; Propanolamines (0) ; Serotonin Plasma Membrane Transport Proteins (0) ; benzimidazol-2-one (43135-91-7) ; Norepinephrine (51-41-2)

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