title: Identification of N-(2-(azepan-1-yl)-2-phenylethyl)-benzenesulfonamides as novel inhibitors of GlyT1.
abstract: A novel series of glycine transporter 1 (GlyT1) inhibitors is described. Scoping of the heterocycle moiety of hit 4-chlorobenzenesulfonamide 1 led to replacement of the piperidine with an azepane for a modest increase in potency. Phenyl sulfonamides proved superior to alkyl and non-phenyl aromatic sulfonamides, while subsequent ortho substitution of the 2-(azepan-1-yl)-2-phenylethanamine aromatic ring yielded 39 (IC(50) 37 nM, solubility 14 microM), the most potent GlyT1 inhibitor in this series. Favorable brain-plasma ratios were observed for select compounds in pharmacokinetic studies to evaluate CNS penetration.
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Varnes
authors.forename: Janet M
authors.initials: JM
authors.lastname: Forst
authors.forename: Tiffany N
authors.initials: TN
authors.lastname: Hoerter
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Holmquist
authors.forename: Deidre E
authors.initials: DE
authors.lastname: Wilkins
authors.forename: Gaochao
authors.initials: G
authors.lastname: Tian
authors.forename: Gerald
authors.initials: G
authors.lastname: Jonak
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: William M
authors.initials: WM
authors.lastname: Potts
authors.forename: Michael W
authors.initials: MW
authors.lastname: Wood
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Alhambra
authors.forename: Todd A
authors.initials: TA
authors.lastname: Brugel
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Albert
mesh_terms: D000818:Animals; D001381:Azepines / Q000737:chemistry; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000096926:Benzenesulfonamides
chemical_list: D001381:Azepines; D001384:Azetidines; D050487:Glycine Plasma Membrane Transport Proteins; D013449:Sulfonamides; D000096926:Benzenesulfonamides