Abstract
The optimization of a series of 5-phenylacetyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives toward the inhibition of Aurora kinases led to the identification of compound 9d. This is a potent inhibitor of Aurora kinases that also shows low nanomolar potency against additional anticancer kinase targets. Based on its high antiproliferative activity on different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, and high efficacy in in vivo tumor models, compound 9d was ultimately selected for further development.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Aurora Kinases
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Male
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Mice
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Models, Molecular
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology
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Solubility
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Pyrazoles
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Pyrroles
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Aurora Kinases
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Protein Serine-Threonine Kinases