title: Discovery of benzylidene derivatives as potent Syk inhibitors: synthesis, SAR analysis, and biological evaluation.
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.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedic, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Dong
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.affiliation: Department of Clinical Pharmacology Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Miao
authors.affiliation: Department of Orthopaedic, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Huang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000072377:Syk Kinase; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D018501:Antirheumatic Agents; D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; C508600:IL6 protein, human; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3
keywords: Antiproliferation; Benzylidene derivatives; Biological evaluation; Rheumatoid arthritis; Syk inhibitors