Potent small molecule inhibitors of spleen tyrosine kinase (Syk).

Bioorganic & medicinal chemistry letters ·Vol. 13 ·No. 18 ·2003-09-15 ·Pages 3111-4

Lai JY, Cox PJ, Patel R, Sadiq S, Aldous DJ, Thurairatnam S, Smith K, Wheeler D, Jagpal S, Parveen S, Fenton G, Harrison TK, McCarthy C, Bamborough P

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).

MeSH Terms

Animals Basophils/drug effects Cell Degranulation/drug effects Cell Line Enzyme Inhibitors/chemistry,pharmacology Enzyme Precursors/antagonists & inhibitors Humans Indoles/chemistry,pharmacology Inhibitory Concentration 50 Intracellular Signaling Peptides and Proteins Oxyquinoline/chemistry,pharmacology Phosphorylation/drug effects Protein-Tyrosine Kinases/antagonists & inhibitors Rats Solubility Structure-Activity Relationship Syk Kinase

Chemicals

Enzyme Inhibitors Enzyme Precursors Indoles Intracellular Signaling Peptides and Proteins Oxyquinoline Protein-Tyrosine Kinases SYK protein, human Syk Kinase Syk protein, rat

Authors & Affiliations

14 authors, click to expand affiliations / ORCID

Lai Justine Y Q

Aventis Pharmaceuticals, Route 202/206, Brigdewater, NJ 08807, USA.

Cox Paul J

Patel Rajesh

Sadiq Shazia

Aldous David J

Thurairatnam Sukanthini

Smith Keith

Wheeler Darren

Jagpal Savita

Parveen Sofia

Fenton Gary

Harrison Trevor K P

McCarthy Clive

Bamborough Paul

Article Info

Journal

Bioorganic & medicinal chemistry letters

Abbr.

Bioorg Med Chem Lett

ISSN

0960-894X

DOI

10.1016/s0960-894x(03)00658-9

Published

2003-09-15

Pages

3111-4

Language

English

Region

England

NLM ID

9107377

Subset

External Links

PubMed source DOI: 10.1016/s0960-894x(03)00658-9 View journal details

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