Abstract
A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of the pharmacokinetic profile of substituted benzimidazoles by reducing their tissue retention. However, the modifications that were necessary to achieve this goal also led to a significant drop in anti-RSV activity. This paper describes a molecular modeling study followed by a lead optimization program that led to the recovery of the initial potent antiviral activity and the selection of TMC353121 as a clinical candidate.
MeSH terms
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Binding Sites
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Drug Resistance, Viral
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Male
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Models, Molecular
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Morpholines / chemical synthesis*
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Morpholines / pharmacokinetics
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Morpholines / pharmacology
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Mutation
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Protein Binding
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Respiratory Syncytial Viruses / drug effects*
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Respiratory Syncytial Viruses / physiology
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Sigmodontinae
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Structure-Activity Relationship
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Viral Fusion Proteins / genetics*
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Virus Internalization / drug effects*
Substances
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2-(6-((2-(3-hydroxypropyl)-5-methylphenylamino)methyl)-2-(3-morpholin-4-ylpropylamino)benzoimidazol-1-ylmethyl)-6-methylpyridin-3-ol
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Antiviral Agents
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Benzimidazoles
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Morpholines
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Pyridines
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Viral Fusion Proteins