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The discovery of potent glycine transporter type-2 inhibitors: Design and synthesis of phenoxymethylbenzamide derivatives |
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| Institution: | 1. Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences, VIT-University, Vellore 632 014, Tamil Nadu, India;2. Trace Elements Speciation Research Laboratory, Environmental and Analytical Chemistry Division, School of Advanced Sciences, VIT-University, Vellore 632 014, Tamil Nadu, India;3. Korea Basic Science Institute, Busan Center, Busan 618 230, South Korea;1. Departamento de Química Inorgánica y Analítica, E.S.C.E.T., Universidad Rey Juan Carlos, 28933 Móstoles, Madrid, Spain;2. Departamento de Química, Universidad del Valle, Calle 13 No 100-00, 76001000 Cali, Colombia;3. Centro de Tecnología Repsol, Autovía de Extremadura A5, km 18, 28935 Móstoles, Madrid, Spain |
| 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, IC50 = 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 (IC50 = 15.3 nM) and exhibited anti-allodynia effects in a mouse neuropathic pain model. |
| Keywords: | Glycine transporter type-2 inhibitor Phenoxymethylbenzamide derivatives Neuropathic pain |
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