Tiffany Hoerter - Identification of N-(2-(azepan-1-yl)-2-phenylethyl)-benzenesulfonamides as novel inhibitors of GlyT1.

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      Publication Details (including relevant citation   information):

    Bioorg Med Chem   Lett. 2010 Aug 15;20(16):4878-81. doi:   10.1016/j.bmcl.2010.06.085. Epub 2010 Jun 19.

    Identification of N-(2-(azepan-1-yl)-2-phenylethyl)-benzenesulfonamides as novel inhibitors of GlyT1.

    Varnes   JG, Forst JM,   Hoerter   TN, Holmquist   CR, Wilkins   DE, Tian G,   Jonak G,   Wang X,   Potts WM,   Wood MW,   Alhambra   C, Brugel   TA, Albert   JS.

    Source

      CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord   Pike, Wilmington, DE 19850, USA.

      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.

      Address (URL): http://www.sciencedirect.com/science/article/pii/S0960894X10008590