Abstract
Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.
Keywords:
HDM201; MDM2-p53 protein-protein interaction (PPI) inhibitors; Pyrrolo[3,4-d]imidazol-4(1H)- ones; Structure guided design; X-ray structure.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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 / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Dogs
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Haplorhini
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Humans
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Male
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Mice
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Microsomes, Liver / metabolism
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Protein Multimerization / drug effects*
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology*
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Pyrrolidinones / chemical synthesis
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Pyrrolidinones / chemistry
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Pyrrolidinones / pharmacokinetics
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Pyrrolidinones / pharmacology*
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Rats, Sprague-Dawley
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Stereoisomerism
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
Substances
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Antineoplastic Agents
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Pyrazoles
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Pyrrolidinones
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TP53 protein, human
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2