title: A novel, non-substrate-based series of glycine type 1 transporter inhibitors derived from high-throughput screening.
abstract: The synthesis and structure-activity relationships (SAR) of a series of indane and tetralin inhibitors of the type 1 glycine transporter, derived from a high-throughput screening (HTS) hit, are described. Key modifications that reduced the 5HT1B receptor affinity of the HTS hit and the P450 2D6 inhibition of subsequent analogues are delineated. While these modifications led to potent and selective GlyT1 inhibitors, HERG affinity and human microsomal clearance remain an issue for this series of compounds.
authors.affiliation: PGRD Groton Laboratories, Pfizer Inc., Groton, CT 06340, USA. john.a.lowe@pfizer.com
authors.forename: J
authors.initials: J
authors.lastname: Lowe
authors.forename: S
authors.initials: S
authors.lastname: Drozda
authors.forename: W
authors.initials: W
authors.lastname: Qian
authors.forename: M-C
authors.initials: MC
authors.lastname: Peakman
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Gibbs
authors.forename: J
authors.initials: J
authors.lastname: Harms
authors.forename: C
authors.initials: C
authors.lastname: Schmidt
authors.forename: K
authors.initials: K
authors.lastname: Fisher
authors.forename: C
authors.initials: C
authors.lastname: Strick
authors.forename: A
authors.initials: A
authors.lastname: Schmidt
authors.forename: M
authors.initials: M
authors.lastname: Vanase
authors.forename: L
authors.initials: L
authors.lastname: Lebel
mesh_terms: D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004353:Drug Evaluation, Preclinical; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D044302:Receptor, Serotonin, 5-HT1B / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D050487:Glycine Plasma Membrane Transport Proteins; C000606913:KCNH2 protein, human; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D044302:Receptor, Serotonin, 5-HT1B; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; C063533:dofetilide