title: Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols.
abstract: A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC(50)=28 nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.
authors.affiliation: Chemical Sciences, Wyeth Research, Arcola Road, Collegeville, PA 19426, USA. kimcy@wyeth.com
authors.forename: Callain Y
authors.initials: CY
authors.lastname: Kim
authors.forename: Paige E
authors.initials: PE
authors.lastname: Mahaney
authors.forename: Oliver
authors.initials: O
authors.lastname: McConnell
authors.forename: Yingru
authors.initials: Y
authors.lastname: Zhang
authors.forename: Eric
authors.initials: E
authors.lastname: Manas
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Ho
authors.forename: Darlene C
authors.initials: DC
authors.lastname: Deecher
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Trybulski
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004285:Dogs; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D008968:Molecular Conformation; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D020005:Propanols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D020005:Propanols; D011994:Recombinant Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D009638:Norepinephrine