Abstract
Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.
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 / pharmacokinetics
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Antiviral Agents / pharmacology*
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Chemistry Techniques, Synthetic
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Crystallography, X-Ray
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Cyclophilins / antagonists & inhibitors*
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Cyclophilins / chemistry
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Cyclophilins / metabolism
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Cyclosporine / chemistry
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Cyclosporine / pharmacology
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Cyclosporins / chemistry
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Cyclosporins / pharmacology*
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Dogs
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Hepacivirus / drug effects
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Hepatitis C / drug therapy
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Humans
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Hydrophobic and Hydrophilic Interactions
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Immunosuppressive Agents / chemistry
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Immunosuppressive Agents / pharmacology
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Liver-Specific Organic Anion Transporter 1
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins / antagonists & inhibitors
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Organic Anion Transporters / antagonists & inhibitors*
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Peptidyl-Prolyl Isomerase F
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Rats
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Structure-Activity Relationship
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Virus Replication / drug effects
Substances
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3-(N-methylalanyl)-4-(4-((tert-butyldiphenylsilyl)oxy)-3-methyl-2-(methylamino)butanoic acid)cyclosporin A
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ABCC2 protein, human
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Antiviral Agents
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Peptidyl-Prolyl Isomerase F
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Cyclosporins
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Immunosuppressive Agents
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Liver-Specific Organic Anion Transporter 1
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins
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Organic Anion Transporters
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SLCO1B1 protein, human
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Cyclosporine
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Cyclophilins
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alisporivir