title: Orally bioavailable Syk inhibitors with activity in a rat PK/PD model.
abstract: Design and optimization of benzo- and pyrido-thiazoles/isothiazoles are reported leading to the discovery of the potent, orally bioavailable Syk inhibitor 5, which was found to be active in a rat PK/PD model. Compound 5 showed acceptable overall kinase selectivity. However, in addition to Syk it also inhibited Aurora kinase in enzymatic and cellular settings leading to findings in the micronucleus assay. As a consequence, compound 5 was not further pursued.
authors: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland. Electronic address: gebhard.thoma@novartis.com.
authors: Gebhard
authors: G
authors: Thoma
authors: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
authors: Siem
authors: S
authors: Veenstra
authors: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
authors: Ross
authors: R
authors: Strang
authors: Analytical Sciences & Imaging, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
authors: Joachim
authors: J
authors: Blanz
authors: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
authors: Eric
authors: E
authors: Vangrevelinghe
authors: Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
authors: Jörg
authors: J
authors: Berghausen
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors: Christian C
authors: CC
authors: Lee
authors: Autoimmunity, Transplantation and Inflammation Research, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
authors: Hans-Günter
authors: HG
authors: Zerwes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D000072377:Syk Kinase; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat
keywords: BIIB-057; Fostamatinib; GS-9973; Kinase inhibitors; Spleen Tyrosine Kinase