Discovery and SAR of novel Naphthyridines as potent inhibitors of spleen tyrosine kinase (SYK).
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.
Cywin
Charles L
CL
Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06801-0368, USA. ccywin@rdg.boehringer-ingelheim.com
Zhao
Bao-Ping
BP
McNeil
Daniel W
DW
Hrapchak
Matt
M
Prokopowicz
Anthony S
AS
Goldberg
Daniel R
DR
Morwick
Tina M
TM
Gao
Amy
A
Jakes
Scott
S
Kashem
Mohammed
M
Magolda
Ronald L
RL
Soll
Richard M
RM
Player
Mark R
MR
Bobko
Mark A
MA
Rinker
James
J
DesJarlais
Renee L
RL
Winters
Michael P
MP
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000201:enzymology*; D013329:Structure-Activity Relationship; D000072377:Syk Kinase
D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase