title: Discovery and SAR of novel Naphthyridines as potent inhibitors of spleen tyrosine kinase (SYK).
abstract: 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.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06801-0368, USA. ccywin@rdg.boehringer-ingelheim.com
authors.forename: Charles L
authors.initials: CL
authors.lastname: Cywin
authors.forename: Bao-Ping
authors.initials: BP
authors.lastname: Zhao
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McNeil
authors.forename: Matt
authors.initials: M
authors.lastname: Hrapchak
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Prokopowicz
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Goldberg
authors.forename: Tina M
authors.initials: TM
authors.lastname: Morwick
authors.forename: Amy
authors.initials: A
authors.lastname: Gao
authors.forename: Scott
authors.initials: S
authors.lastname: Jakes
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kashem
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Magolda
authors.forename: Richard M
authors.initials: RM
authors.lastname: Soll
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bobko
authors.forename: James
authors.initials: J
authors.lastname: Rinker
authors.forename: Renee L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: Michael P
authors.initials: MP
authors.lastname: Winters
mesh_terms: 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
chemical_list: 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