Discovery of 2-ethoxy-4-(methoxymethyl)benzamide derivatives as potent and selective PTP1B inhibitors |
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| Affiliation: | 1. Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University (SJTU), 800 Dongchuan Road, Shanghai 200240, China;2. Viva Biotech (Shanghai) Limited, Shanghai 201203, China;1. School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China;2. School of Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, PR China;1. School of Life Science and Biotechnology, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China;2. School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China;1. School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd., Shanghai 200240, China;2. Department of Chemistry, University of Florida, Gainesville, FL, 32611-7200, USA;1. School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Minhang District, Shanghai 200240, China;2. China State Institute of Pharmaceutical Industry, No. 285 Gebaini Rd., Pudong District, Shanghai 201203, China;3. Viva Biotech Ltd. (Shanghai), No. 334 Aidisheng Rd., Pudong District, Shanghai 201203, China;4. Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 369 Zhizaoju Road, Huangpu District, Shanghai 200011, China;5. Xinhua Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Rd., Yangpu District, Shanghai 200092, China;1. Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University (SJTU), Shanghai, China;2. SJTU-Agilent Technologies Joint Laboratory for Pharmaceutical Analysis, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China;3. Academy of Pharmacy, Xi''an Jiaotong – Liverpool University, Suzhou, 215123, China;1. Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China;2. Department of Biological Sciences, Faculty of Science, National University of Singapore, 16 Science Drive 4, 117558, Singapore |
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| Abstract: | Protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of insulin signaling, is considered as a promising and validated therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. Upon careful study, a series of 2-ethoxy-4-(methoxymethyl)benzamide and 2-ethoxy-5-(methoxymethyl)benzamide analogs designed by the “bioisosteric principle” were discovered, wherein their PTP1B inhibitory potency, type of PTP1B inhibition, selectivity and membrane permeability were evaluated. Among them, compound 10m exhibited high inhibitory activity (IC50 = 0.07 μM), significant selectivity (32-fold) over T-cell PTPase (TCPTP) as well as good membrane permeability (Papp = 2.41 × 10−6 cm/s). Further studies on cell viability and cellular activity revealed that compound 10m could enhance insulin-stimulated glucose uptake with no significant cytotoxicity. |
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| Keywords: | PTP1B Inhibitors Selectivity 2-Ethoxy-4-(methoxymethyl)benzamide Type 2 diabetes |
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