Abstract
The structure-based design, synthesis, and biological evaluation of two novel series of potent and selective MEK kinase inhibitors are described herein. The elaboration of a lead pyrrole derivative to a bicyclic dihydroindolone core provided compounds with high potency and good drug-like pharmaceutical properties. Further scaffold modification afforded a series of dihydroindolizinone inhibitors, including an orally available advanced preclinical MEK inhibitor with potent in vivo antitumor efficacy.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / therapeutic use
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Drug Design
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HT29 Cells
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Humans
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Indolizines / administration & dosage
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Indolizines / chemical synthesis*
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Indolizines / therapeutic use
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MAP Kinase Kinase Kinases / antagonists & inhibitors*
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MAP Kinase Kinase Kinases / metabolism
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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 / therapeutic use
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Pyrroles / administration & dosage
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Pyrroles / chemical synthesis*
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Pyrroles / therapeutic use
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Rats
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Indolizines
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Protein Kinase Inhibitors
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Pyrroles
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MAP Kinase Kinase Kinases