Identification of N-(2-(azepan-1-yl)-2-phenylethyl)-benzenesulfonamides as novel inhibitors of GlyT1.
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.
Varnes
Jeffrey G
JG
CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA.
Forst
Janet M
JM
Hoerter
Tiffany N
TN
Holmquist
Christopher R
CR
Wilkins
Deidre E
DE
Tian
Gaochao
G
Jonak
Gerald
G
Wang
Xia
X
Potts
William M
WM
Wood
Michael W
MW
Alhambra
Cristóbal
C
Brugel
Todd A
TA
Albert
Jeffrey S
JS
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
D001381:Azepines; D001384:Azetidines; D050487:Glycine Plasma Membrane Transport Proteins; D013449:Sulfonamides; D000096926:Benzenesulfonamides