Design,Synthesis, and Structure–Activity Relationship Study of Potent MAPK11 Inhibitors |
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| Authors: | Mengdie Gong Mingyan Tu Hongxia Sun Lu Li Lili Zhu Honglin Li Zhenjiang Zhao Shiliang Li |
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| Affiliation: | 1.Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China; (M.G.); (M.T.); (H.S.); (L.L.); (L.Z.); (H.L.);2.Jiangzhong Pharmaceutical Co., Ltd., Nanchang 330096, China |
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| Abstract: | Huntington’s disease (HD) is a rare single-gene neurodegenerative disease, which can only be treated symptomatically. Currently, there are no approved drugs for HD on the market. Studies have found that MAPK11 can serve as a potential therapeutic target for HD. Regrettably, no MAPK11 small molecule inhibitors have been approved at present. This paper presents three series of compounds that were designed and synthesized based on the structure of skepinone-L, a known MAPK14 inhibitor. Among the synthesized compounds, 13a and 13b, with IC50 values of 6.40 nM and 4.20 nM, respectively, displayed the best inhibitory activities against MAPK11. Furthermore, the structure–activity relationship (SAR) is discussed in detail, which is constructive in optimizing the MAPK11 inhibitors for better activity and effect against HD. |
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| Keywords: | MAPK11, Huntington’ s disease, mHTT protein, inhibitors |
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