Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B |
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| Authors: | Hai-Bing He Li-Xin Gao Qi-Feng Deng Wei-Ping Ma Chun-Lan Tang Wen-Wei Qiu Jie Tang Jing-Ya Li Jia Li Fan Yang |
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| Affiliation: | 1. Shanghai Engineering Research Center of Molecular Theraputics and New Drug Development, East China Normal University, Shanghai 200062, China;2. Institute of Medicinal Chemistry and Department of Chemistry, East China Normal University, Shanghai 200062, China;3. National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China |
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| Abstract: | Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both insulin and leptin signals. For years, inhibiting of PTP1B has been considered to be a potential therapeutics for treating Type 2 diabetes and obesity. Recently, we recognized lithocholic acid (LCA) as a natural inhibitor against PTP1B (IC50 = 12.74 μM) by a vertical screen for the first time. Further SAR research was carried out by synthesizing and evaluating a series of compounds bearing two methyls at C-4 position and a fused heterocycle to ring A. Among them, compound 14b achieved a PTP1B inhibitory activity about eightfold than LCA and a 14-fold selectivity over the homogenous enzyme TCPTP. |
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