Abstract
Described herein is a new approach to mitigate CYP3A4 induction. In this unconventional approach, a fine-tuning of the dihedral angle between the C4 phenyl and the dihydropyrimidine core of the heteroaryldihydropyrimidine (HAP) class of capsid inhibitors successfully altered the structure-activity-relationships (SARs) of the unwanted CYP3A4 induction and the desired HBV capsid inhibition to more favorable values. This eventually led to the discovery of a new capsid inhibitor with significantly reduced CYP3A4 induction, excellent anti-HBV activity, favorable preclinical PK/PD profiles, and no early safety flags.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology*
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Capsid / drug effects*
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Crystallography, X-Ray
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Cytochrome P-450 CYP1A2 Inducers / chemistry
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Cytochrome P-450 CYP1A2 Inducers / pharmacology
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Cytochrome P-450 CYP2B6 Inducers / chemistry
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Cytochrome P-450 CYP2B6 Inducers / pharmacology
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Cytochrome P-450 CYP3A / chemistry
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Cytochrome P-450 CYP3A Inducers / chemistry
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Cytochrome P-450 CYP3A Inducers / pharmacology*
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Dose-Response Relationship, Drug
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Enzyme Induction / drug effects
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Female
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Hepatitis B virus / drug effects*
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Hepatocytes / drug effects
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Hepatocytes / enzymology
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Humans
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Mice, Inbred BALB C
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Pregnane X Receptor / metabolism*
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Rats
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Structure-Activity Relationship
Substances
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Antiviral Agents
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Cytochrome P-450 CYP1A2 Inducers
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Cytochrome P-450 CYP2B6 Inducers
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Cytochrome P-450 CYP3A Inducers
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NR1I2 protein, human
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Pregnane X Receptor
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Cytochrome P-450 CYP3A