title: Discovery and profiling of a selective and efficacious Syk inhibitor.
abstract: We describe the discovery of selective and potent Syk inhibitor 11, which exhibited favorable PK profiles in rat and dog and was found to be active in a collagen-induced arthritis model in rats. Compound 11 was selected for further profiling, but, unfortunately, in GLP toxicological studies it showed liver findings in rat and dog. Nevertheless, 11 could become a valuable tool compound to investigate the rich biology of Syk in vitro and in vivo.
authors: Global Discovery Chemistry, ‡Analytical Sciences & Imaging, §Autoimmunity, Transplantation and Inflammation Research, Novartis Institutes for Biomedical Research , 4056 Basel, Switzerland.
authors: Gebhard
authors: G
authors: Thoma
authors: Alexander B
authors: AB
authors: Smith
authors: Maurice J
authors: MJ
authors: van Eis
authors: Eric
authors: E
authors: Vangrevelinghe
authors: Joachim
authors: J
authors: Blanz
authors: Reiner
authors: R
authors: Aichholz
authors: Amanda
authors: A
authors: Littlewood-Evans
authors: Christian C
authors: CC
authors: Lee
authors: Hong
authors: H
authors: Liu
authors: Hans-Günter
authors: HG
authors: Zerwes
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D003094:Collagen; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D000072377:Syk Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D003094:Collagen; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C000606898:Syk protein, rat