Abstract
This Letter reports the optimization of a pyrrolopyrimidine series as dual inhibitors of Aurora A/B kinases. This series derived from a pyrazolopyrimidine series previously reported as inhibitors of aurora kinases and CDKs. In an effort to improve the selectivity of this chemotype, we switched to the pyrrolopyrimidine core which allowed functionalization on C-2. In addition, the modeling rationale was based on superimposing the structures of Aurora-A kinase and CDK2 which revealed enough differences leading to a path for selectivity improvement. The synthesis of the new series of pyrrolopyrimidine analogs relied on the development of a different route for the two key intermediates 7 and 19 which led to analogs with both tunable activity against CDK1 and maintained cell potency.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Aurora Kinases
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Binding Sites
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CDC2 Protein Kinase / chemistry*
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Cell Cycle Checkpoints / drug effects
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Cell Line
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Cyclin-Dependent Kinase 2 / chemistry*
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Drug Design
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Humans
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Models, Molecular
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Molecular Structure
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacology
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Structural Homology, Protein
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyrimidines
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Pyrroles
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Aurora Kinases
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Protein Serine-Threonine Kinases
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CDC2 Protein Kinase
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Cyclin-Dependent Kinase 2