title: Discovery of 1-(3,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine, a dual serotonin and dopamine reuptake inhibitor.
abstract: The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis and in vitro activity and ADME profile of the compounds is described, which represent a previously undisclosed dual reuptake inhibitor chemotype.
authors.affiliation: Discovery and Early Clinical Research, Sunovion Pharmaceuticals Inc, 84 Waterford Drive, Marlborough, MA 01752, USA. liming.shao@sunovion.com
authors.forename: Liming
authors.initials: L
authors.lastname: Shao
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ma
authors.forename: Fengjiang
authors.initials: F
authors.lastname: Wang
authors.forename: Scott C
authors.initials: SC
authors.lastname: Malcolm
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hewitt
authors.forename: Una C
authors.initials: UC
authors.lastname: Campbell
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Spicer
authors.forename: Larry W
authors.initials: LW
authors.lastname: Hardy
authors.forename: Rudy
authors.initials: R
authors.lastname: Schreiber
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Spear
authors.forename: Mark A
authors.initials: MA
authors.lastname: Varney
mesh_terms: D000818:Animals; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D011804:Quinolines; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C557269:1-(3,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine