Discovery of benzylidene derivatives as potent Syk inhibitors: synthesis, SAR analysis, and biological evaluation.

Lingling Zhang, Wei Liu, Fei Mao, Jin Zhu, Guoqiang Dong, Hualiang Jiang, Chunquan Sheng, Liyan Miao, Lixin Huang, Jian Li

Index: Arch. Pharm. (Weinheim) 348 , 463-74, (2015)

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Abstract

Four scaffolds of varied benzylidene derivatives were synthesized and evaluated as Syk inhibitors for the treatment of rheumatoid arthritis (RA). Among these 31 compounds, 3-benzylidene pyrrolidine-2,5-dione derivatives (including 12k) universally showed good Syk inhibitory activities in the low micromolar to submicromolar range. In the cellular profiling, compound 12k, the most efficient compound, showed excellent antiproliferative activity against fibroblast-like synoviocytes (FLS)-RA, and demonstrated potencies for suppression of IL-6 and MMP-3 secretion almost equal to R406 (positive control). The oral efficacy of 12k in the murine collagen-induced arthritis model was significant, despite being weaker than R406. Taken together, all preliminary pharmacological results supported 12k as a potential small-molecule inhibitor targeting Syk for the treatment of RA. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.