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Orally bioavailable Syk inhibitors with activity in a rat PK/PD model.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Oct 15; Vol. 25 (20), pp. 4642-7. Date of Electronic Publication: 2015 Aug 18. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Administration, Oral
Animals
Biological Availability
Dose-Response Relationship, Drug
Intracellular Signaling Peptides and Proteins metabolism
Microsomes, Liver drug effects
Microsomes, Liver metabolism
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors chemistry
Protein-Tyrosine Kinases metabolism
Rats
Rats, Inbred Lew
Rats, Sprague-Dawley
Structure-Activity Relationship
Syk Kinase
Thiazoles administration & dosage
Thiazoles chemistry
Disease Models, Animal
Intracellular Signaling Peptides and Proteins antagonists & inhibitors
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors pharmacology
Protein-Tyrosine Kinases antagonists & inhibitors
Thiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 25
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 26320624
- Full Text :
- https://doi.org/10.1016/j.bmcl.2015.08.037