Discovery of novel free fatty acid receptor 1 agonists bearing triazole core via click chemistry |
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| Affiliation: | 1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;1. Department of Chemistry, New York University, New York, NY 10003, USA;2. Nanometics LLC, 111 Great Neck Rd, Suite 212, Great Neck, NY 11021, USA;3. Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA;4. Department of Radiology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA;1. Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5, Murmanska, 02094 Kiev, Ukraine;2. Institute of Bioorganic Chemistry & Petrochemistry, National Academy of Sciences of Ukraine, 1, Murmanska, 02660 Kiev, Ukraine;1. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;2. School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China;3. School of Pharmacy, Fudan University, Shanghai 201203, China;1. Department of Clinical Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China;2. Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China |
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| Abstract: | The free fatty acid receptor 1 (FFA1/GPR40) is a novel antidiabetic target based on particular mechanism in enhancing glucose-stimulated insulin secretion. Most of reported FFA1 agonists, however, have been suffered from relatively high lipophilicity and molecular weight. Aiming to develop potent agonists with improved physicochemical property, 25 compounds containing triazole scaffold and various carboxylic acid fragments were synthesized via the click chemistry. Among them, the optimal lead compound 26 with relatively low lipophicity (Log D7.4 = 1.95) and molecular weight (Mw = 391.78) exhibited a considerable FFA1 agonistic activity (36.15%). In addition, compound 26 revealed a significant improvement in the glucose tolerance with a 21.4% and 14.2% reduction of glucose AUC0–2h in normal ICR mice and type 2 diabetic C57BL/6 mice, respectively. All of these results demonstrated that compound 26 was considered to be a promising lead compound suitable for further optimization. |
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| Keywords: | FFA1 agonist GPR40 Triazole core Click chemistry Type 2 diabetes |
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