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Discovery of Benzylidene Derivatives as Potent Syk Inhibitors: Synthesis, SAR Analysis, and Biological Evaluation
Author(s) -
Zhang Lingling,
Liu Wei,
Mao Fei,
Zhu Jin,
Dong Guoqiang,
Jiang Hualiang,
Sheng Chunquan,
Miao Liyan,
Huang Lixin,
Li Jian
Publication year - 2015
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201500096
Subject(s) - syk , chemistry , rheumatoid arthritis , pharmacology , fibroblast , arthritis , pyrrolidine , virtual screening , structure–activity relationship , lead compound , drug discovery , in vitro , receptor , biochemistry , stereochemistry , medicine , tyrosine kinase
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.