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

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

Author information

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.

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

PMID:
26320624
DOI:
10.1016/j.bmcl.2015.08.037
[Indexed for MEDLINE]

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