Discovery of novel Syk/PDGFR-α/c-Kit inhibitors as multi-targeting drugs to treat rheumatoid arthritis

Bioorg Med Chem. 2018 Aug 15;26(15):4375-4381. doi: 10.1016/j.bmc.2018.06.029.

Xiaokang Li ¹, Yahui Huang ², Junfei Cheng ², Lingling Zhang ¹, Fei Mao ¹, Jin Zhu ¹, Chunquan Sheng ³, Jian Li ⁴

Affiliations

1 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China.
2 Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
3 Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China. Electronic address: shengcq@smmu.edu.cn.
4 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China. Electronic address: jianli@ecust.edu.cn.

PMID: 30078608 DOI: 10.1016/j.bmc.2018.06.029

Abstract

Due to the complex biological pathways involved in rheumatoid arthritis, discovery of multi-targeting small molecules provides an effective strategy to achieve better efficacy and lower toxicity. Herein the first Syk/PDGFR-α/c-Kit inhibitors were designed and evaluated. Dihydrofuropyrimidine derivative 13 showed potent inhibitory activity against the three targets. Importantly, compound 13 exhibited good cellular efficacy against fibroblast-like synoviocytes (IC₅₀ = 3.21 μM) and mouse bone marrow-derived mast cells (IC₅₀ = 2.03 μM) and significantly decreased the secretion of inflammatory cytokines. Thus, Syk/PDGFR-α/c-Kit triple inhibitor 13 represented a promising lead compound for the treatment of RA.

Keywords

Dihydrofuropyrimidines; Multi-targeting inhibitors; PDGFR-α; Rheumatoid arthritis; Syk; c-Kit.

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