Orally bioavailable Syk inhibitors with activity in a rat PK/PD model

Gebhard Thoma; Siem Veenstra; Ross Strang; Joachim Blanz; Eric Vangrevelinghe; Jörg Berghausen; Christian C Lee; Hans-Günter Zerwes

doi:10.1016/j.bmcl.2015.08.037

Orally bioavailable Syk inhibitors with activity in a rat PK/PD model

Bioorg Med Chem Lett. 2015 Oct 15;25(20):4642-7. doi: 10.1016/j.bmcl.2015.08.037. Epub 2015 Aug 18.

Authors

Gebhard Thoma¹, Siem Veenstra², Ross Strang², Joachim Blanz³, Eric Vangrevelinghe², Jörg Berghausen⁴, Christian C Lee⁵, Hans-Günter Zerwes⁶

Affiliations

¹ Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland. Electronic address: gebhard.thoma@novartis.com.
² Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
³ Analytical Sciences & Imaging, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
⁴ Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
⁵ Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
⁶ Autoimmunity, Transplantation and Inflammation Research, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.

PMID: 26320624
DOI: 10.1016/j.bmcl.2015.08.037

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.

Keywords: BIIB-057; Fostamatinib; GS-9973; Kinase inhibitors; Spleen Tyrosine Kinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Biological Availability
Disease Models, Animal*
Dose-Response Relationship, Drug
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / metabolism
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / administration & dosage*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Rats
Rats, Inbred Lew
Rats, Sprague-Dawley
Structure-Activity Relationship
Syk Kinase
Thiazoles / administration & dosage
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Thiazoles
Protein-Tyrosine Kinases
Syk Kinase
Syk protein, rat