Design, Synthesis and SAR Studies of Novel and Potent Dipeptidyl Peptidase 4 Inhibitors
Na Luo
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237 China
Search for more papers by this authorXiaoyu Fang
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237 China
Search for more papers by this authorMingbo Su
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zhuchongzhi Road, Shanghai, 201203 China
Search for more papers by this authorXinwen Zhang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zhuchongzhi Road, Shanghai, 201203 China
Search for more papers by this authorDan Li
Shandong Biopolar Dichang Pharmaceutical Co., Ltd., RM2306, No. 786 Linzi Avenue, Zibo, Shandong, 255400 China
Search for more papers by this authorHonglin Li
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237 China
Search for more papers by this authorCorresponding Author
Shiliang Li
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237 China
E-mail: [email protected], [email protected]Search for more papers by this authorCorresponding Author
Zhenjiang Zhao
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237 China
E-mail: [email protected], [email protected]Search for more papers by this authorNa Luo
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237 China
Search for more papers by this authorXiaoyu Fang
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237 China
Search for more papers by this authorMingbo Su
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zhuchongzhi Road, Shanghai, 201203 China
Search for more papers by this authorXinwen Zhang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zhuchongzhi Road, Shanghai, 201203 China
Search for more papers by this authorDan Li
Shandong Biopolar Dichang Pharmaceutical Co., Ltd., RM2306, No. 786 Linzi Avenue, Zibo, Shandong, 255400 China
Search for more papers by this authorHonglin Li
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237 China
Search for more papers by this authorCorresponding Author
Shiliang Li
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237 China
E-mail: [email protected], [email protected]Search for more papers by this authorCorresponding Author
Zhenjiang Zhao
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237 China
E-mail: [email protected], [email protected]Search for more papers by this authorMain observation and conclusion
Dipeptidyl peptidase 4 (DPP-4) is a clinically validated target for the treatment of type 2 diabetes mellitus (T2DM). To discover novel and potent DPP-4 inhibitors, three series of compounds were designed and synthesized in this study based on our previously identified novel scaffold of 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine. Among the designed compounds, 41d-1 was the most potent one with an IC50 value of 16.00 nM. Besides, 41d-1 (5 mg/kg) displayed a moderate glucose tolerance capability in ICR mice. Structure-activity-relationship (SAR) studies were discussed in detail, which is constructive for our further optimization.
Supporting Information
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Appendix S1: Supporting Information |
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References
- 1IDF Diabetes Atlas. http://www.idf.org/diabetesatlas (accessed Nov 15, 2019).
- 2 Chatterjee, S.; Khunti, K.; Davies, M. J. Type 2 diabetes. Lancet 2017, 389, 2239–2251.
- 3 Cavender, M. A.; Steg, P. G.; Smith, S. C., Jr.; Eagle, K.; Ohman, E. M.; Goto, S.; Kuder, J.; Im, K.; Wilson, P. W.; Bhatt, D. L.; Investigators, R. R. Impact of Diabetes Mellitus on Hospitalization for Heart Failure, Cardiovascular Events, and Death: Outcomes at 4 Years From the Reduction of Atherothrombosis for Continued Health (REACH) Registry. Circulation 2015, 132, 923–931.
- 4 Hu, C.; Jia, W. Therapeutic medications against diabetes: What we have and what we expect. Adv. Drug Deliv. Rev. 2019, 139, 3–15.
- 5 Proenca, C.; Freitas, M.; Ribeiro, D.; Tome, S. M.; Araujo, A. N.; Silva, A. M. S.; Fernandes, P. A.; Fernandes, E. The dipeptidyl peptidase-4 inhibitory effect of flavonoids is hindered in protein rich environments. Food Funct. 2019, 10, 5718–5731.
- 6 Waldrop, G.; Zhong, J.; Peters, M.; Rajagopalan, S. Incretin-Based Therapy for Diabetes: What a Cardiologist Needs to Know. J. Am. Coll. Cardiol. 2016, 67, 1488–1496.
- 7 Baggio, L. L.; Drucker, D. J. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007, 132, 2131–2157.
- 8 Patel, B. D.; Ghate, M. D. Recent approaches to medicinal chemistry and therapeutic potential of dipeptidyl peptidase-4 (DPP-4) inhibitors. Eur. J. Med. Chem. 2014, 74, 574–605.
- 9 Zhong, J.; Gong, Q.; Goud, A.; Srinivasamaharaj, S.; Rajagopalan, S. Recent Advances in Dipeptidyl-Peptidase-4 Inhibition Therapy: Lessons from the Bench and Clinical Trials. J. Diabetes Res. 2015, 2015, 606031.
- 10 Almagthali, A. G.; Alkhaldi, E. H.; Alzahrani, A. S.; Alghamdi, A. K.; Alghamdi, W. Y.; Kabel, A. M. Dipeptidyl peptidase-4 inhibitors: Anti-diabetic drugs with potential effects on cancer. Diabetes Metab. Syndr. 2019, 13, 36–39.
- 11 Li, S.; Xu, H.; Cui, S.; Wu, F.; Zhang, Y.; Su, M.; Gong, Y.; Qiu, S.; Jiao, Q.; Qin, C.; Shan, J.; Zhang, M.; Wang, J.; Yin, Q.; Xu, M.; Liu, X.; Wang, R.; Zhu, L.; Li, J.; Xu, Y.; Jiang, H.; Zhao, Z.; Li, J.; Li, H. Discovery and Rational Design of Natural-Product-Derived 2-Phenyl-3,4-dihydro-2H- benzo f chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes. J. Med. Chem. 2016, 59, 6772–6790.
- 12 Li, S.; Qin, C.; Cui, S.; Xu, H.; Wu, F.; Wang, J.; Su, M.; Fang, X.; Li, D.; Jiao, Q. Discovery of a natural-product-derived preclinical candidate for once-weekly treatment of type 2 diabetes. J. Med. Chem. 2019, 62, 2348–2361.
- 13 Biftu, T.; Sinha-Roy, R.; Chen, P.; Qian, X.; Feng, D.; Kuethe, J. T.; Scapin, G.; Gao, Y. D.; Yan, Y.; Krueger, D.; Bak, A.; Eiermann, G.; He, J.; Cox, J.; Hicks, J.; Lyons, K.; He, H.; Salituro, G.; Tong, S.; Patel, S.; Doss, G.; Petrov, A.; Wu, J.; Xu, S. S.; Sewall, C.; Zhang, X.; Zhang, B.; Thornberry, N. A.; Weber, A. E. Omarigliptin (MK-3102): A Novel Long-Acting DPP-4 Inhibitor for Once-Weekly Treatment of Type 2 Diabetes. J. Med. Chem. 2014, 57, 3205–3212.
- 14 Moseley, J. D.; Sankey, R. F.; Tang, O. N.; Gilday, J. P. The Newman- Kwart rearrangement re-evaluated by microwave synthesis. Tetrahedron 2006, 62, 4685–4689.
