Discovery and SAR of novel [1,6]Naphthyridines as potent inhibitors of spleen tyrosine kinase (SYK)

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 8; pp. 1415 - 1418
• Main Authors: Cywin, Charles L, Zhao, Bao-Ping, McNeil, Daniel W, Hrapchak, Matt, Prokopowicz, Anthony S, Goldberg, Daniel R, Morwick, Tina M, Gao, Amy, Jakes, Scott, Kashem, Mohammed, Magolda, Ronald L, Soll, Richard M, Player, Mark R, Bobko, Mark A, Rinker, James, DesJarlais, Renee L, Winters, Michael P
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 17.04.2003; Elsevier
• Subjects: Animals; Biological and medical sciences; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Precursors - antagonists & inhibitors; Humans; Inhibitory Concentration 50; Intracellular Signaling Peptides and Proteins; Medical sciences; Miscellaneous; Naphthyridines - chemistry; Naphthyridines - pharmacology; Pharmacology. Drug treatments; Protein-Tyrosine Kinases - antagonists & inhibitors; Spleen - enzymology; Structure-Activity Relationship; Syk Kinase; Phosphorylation; Enzyme; Nitrogen heterocycle; Transferases; Enzyme inhibitor; In vitro; Diamine; Signal transduction; Structure activity relation; Bicyclic compound; Naphtyridine derivatives; Chemical synthesis; Protein-tyrosine kinase; Aromatic amine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00163-X

The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail. Graphic