Abstract
The discovery and lead optimisation of a novel series of SYK inhibitors is described. These were optimised for SYK potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials.
Keywords:
Dermal; Inhibitor; Lead optimisation; SYK; Skin penetration; Spleen Tyrosine Kinase.
Copyright © 2018 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Topical
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Anti-Inflammatory Agents / administration & dosage
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology*
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Catalytic Domain
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Cell Line, Tumor
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Humans
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Molecular Docking Simulation
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Molecular Structure
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Pyridines / administration & dosage
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / pharmacology*
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Skin / drug effects*
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Structure-Activity Relationship
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Syk Kinase / antagonists & inhibitors*
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Syk Kinase / chemistry
Substances
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Anti-Inflammatory Agents
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GSK2646264
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Protein Kinase Inhibitors
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Pyridines
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SYK protein, human
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Syk Kinase