title: Potent small molecule inhibitors of spleen tyrosine kinase (Syk).
abstract: A series of oxindoles demonstrating inhibition of the phosphorylation of biotinylated substrates of Syk and IgE/Fc epsilon RI triggered basophil cell degranulation has been identified. A study of the SAR around sulfonamide 31 (IC(50)=5 nM, EC(50)=1400 nM) is discussed. The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM).
authors.affiliation: Aventis Pharmaceuticals, Route 202/206, Brigdewater, NJ 08807, USA.
authors.forename: Justine Y Q
authors.initials: JY
authors.lastname: Lai
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Cox
authors.forename: Rajesh
authors.initials: R
authors.lastname: Patel
authors.forename: Shazia
authors.initials: S
authors.lastname: Sadiq
authors.forename: David J
authors.initials: DJ
authors.lastname: Aldous
authors.forename: Sukanthini
authors.initials: S
authors.lastname: Thurairatnam
authors.forename: Keith
authors.initials: K
authors.lastname: Smith
authors.forename: Darren
authors.initials: D
authors.lastname: Wheeler
authors.forename: Savita
authors.initials: S
authors.lastname: Jagpal
authors.forename: Sofia
authors.initials: S
authors.lastname: Parveen
authors.forename: Gary
authors.initials: G
authors.lastname: Fenton
authors.forename: Trevor K P
authors.initials: TK
authors.lastname: Harrison
authors.forename: Clive
authors.initials: C
authors.lastname: McCarthy
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
mesh_terms: D000818:Animals; D001491:Basophils / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D015125:Oxyquinoline / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D000072377:Syk Kinase
chemical_list: D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D015125:Oxyquinoline; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat