title: Synthesis and structure-activity relationships of a series of 4-methoxy-3-(piperidin-4-yl)oxy benzamides as novel inhibitors of the presynaptic choline transporter.
abstract: The synthesis and SAR of 4-methoxy-3-(piperidin-4-yl) benzamides identified after a high-throughput screen of the MLPCN library is reported. SAR was explored around the 3-piperidine substituent as well as the amide functionality of the reported compounds. Starting from the initial lead compounds, 1-7, iterative medicinal chemistry efforts led to the identification of ML352 (10m). ML352 represents a potent and selective inhibitor of CHT based on a drug-like scaffold.
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Sean R
authors: SR
authors: Bollinger
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Darren W
authors: DW
authors: Engers
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Elizabeth A
authors: EA
authors: Ennis
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Jane
authors: J
authors: Wright
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Charles W
authors: CW
authors: Locuson
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Craig W
authors: CW
authors: Lindsley
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Randy D
authors: RD
authors: Blakely
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA. Electronic address: corey.r.hopkins@vanderbilt.edu.
authors: Corey R
authors: CR
authors: Hopkins
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; D026901:Membrane Transport Proteins; D010880:Piperidines; C510731:SLC5A7 protein, human; D027981:Symporters; C065637:choline transporter; C032727:piperidine
keywords: CHT; Choline transporter; ML352; MLPCN; Structure–activity relationship