Potent small molecule inhibitors of spleen tyrosine kinase (Syk).
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).
Lai
Justine Y Q
JY
Aventis Pharmaceuticals, Route 202/206, Brigdewater, NJ 08807, USA.
Cox
Paul J
PJ
Patel
Rajesh
R
Sadiq
Shazia
S
Aldous
David J
DJ
Thurairatnam
Sukanthini
S
Smith
Keith
K
Wheeler
Darren
D
Jagpal
Savita
S
Parveen
Sofia
S
Fenton
Gary
G
Harrison
Trevor K P
TK
McCarthy
Clive
C
Bamborough
Paul
P
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
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