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.
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.
authors.affiliation: Chemical Sciences, Wyeth Research, S-2250B, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. Zhangp@wyeth.com
authors.forename: Puwen
authors.initials: P
authors.lastname: Zhang
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Terefenko
authors.forename: Jenifer
authors.initials: J
authors.lastname: Bray
authors.forename: Darlene
authors.initials: D
authors.lastname: Deecher
authors.forename: Andrew
authors.initials: A
authors.lastname: Fensome
authors.forename: Jim
authors.initials: J
authors.lastname: Harrison
authors.forename: Callain
authors.initials: C
authors.lastname: Kim
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Koury
authors.forename: Lilly
authors.initials: L
authors.lastname: Mark
authors.forename: Casey C
authors.initials: CC
authors.lastname: McComas
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Mugford
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Trybulski
authors.forename: An T
authors.initials: AT
authors.lastname: Vu
authors.forename: Garth T
authors.initials: GT
authors.lastname: Whiteside
authors.forename: Paige E
authors.initials: PE
authors.lastname: Mahaney
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D011412:Propanolamines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013127:Spinal Nerves / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D001562:Benzimidazoles; D050483:Dopamine Plasma Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011412:Propanolamines; D050486:Serotonin Plasma Membrane Transport Proteins; C053110:benzimidazol-2-one; D009638:Norepinephrine