The discovery of potent glycine transporter type-2 inhibitors: Design and synthesis of phenoxymethylbenzamide derivatives

Abstract We describe the discovery of phenoxymethylbenzamide derivatives as a novel class of glycine transporter type-2 (GlyT-2) inhibitors. We found hit compound 1 (human GlyT-2, IC 50  = 4040 nM) in our library and converted its 1-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)pyrrolidin-3-yl group to an 1-( N , N -dimethylaminopropyl)piperidyl group and its tert -butyl group to a trifluoromethyl group to obtain N -(1-(3-(dimethylamino)propyl)piperidin-4-yl)-4-((4-(trifluoromethyl)phenoxy)methyl)benzamide ( 20 ). Compound 20 showed good inhibitory activity against human GlyT-2 (IC 50  = 15.3 nM) and exhibited anti-allodynia effects in a mouse neuropathic pain model.