Bicyclo((aryl)methyl)benzamides as inhibitors of GlyT1

• Published in: Bioorganic & medicinal chemistry letters 2018-04, Vol.28 (6), p.1043-1049
• Main Authors: Varnes, Jeffrey G., Xiong, Hui, Forst, Janet M., Holmquist, Christopher R., Ernst, Glen E., Frietze, William, Dembofsky, Bruce, Andisik, Don W., Palmer, William E., Hinkley, Lindsay, Steelman, Gary B., Wilkins, Deidre E., Tian, Gaochao, Jonak, Gerald, Potts, William M., Wang, Xia, Brugel, Todd A., Alhambra, Cristóbal, Wood, Michael W., Veale, Chris A., Albert, Jeffrey S.
• Format: Article
• Language: English
• Subjects: Glycine uptake inhibition; GlyT1; N-Methyl-d-aspartate receptor; NMDAr; Schizophrenia
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.02.029

A series of isoquinuclidines and bicyclic analogs were investigated as inhibitors of glycine uptake for the treatment of schizophrenia. Dimethylbenzamide 9 exhibited a dose-dependent response in a mouse MK801 locomotor assay as a model of the positive and negative symptoms of schizophrenia. [Display omitted] A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40–41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 μmol/kg compared to control.