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Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition.

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.
AuthorsJiping Fu, Meiliana Tjandra, Christopher Becker, Dallas Bednarczyk, Michael Capparelli, Robert Elling, Imad Hanna, Roger Fujimoto, Markus Furegati, Subramanian Karur, Theresa Kasprzyk, Mark Knapp, Kwan Leung, Xiaolin Li, Peichao Lu, Wosenu Mergo, Charlotte Miault, Simon Ng, David Parker, Yunshan Peng, Silvio Roggo, Alexey Rivkin, Robert L Simmons, Michael Wang, Brigitte Wiedmann, Andrew H Weiss, Linda Xiao, Lili Xie, Wenjian Xu, Aregahegn Yifru, Shengtian Yang, Bo Zhou, Zachary K Sweeney
JournalJournal of medicinal chemistry (J Med Chem) Vol. 57 Issue 20 Pg. 8503-16 (Oct 23 2014) ISSN: 1520-4804 [Electronic] United States
PMID25310383 (Publication Type: Journal Article)
Chemical References
  • 3-(N-methylalanyl)-4-(4-((tert-butyldiphenylsilyl)oxy)-3-methyl-2-(methylamino)butanoic acid)cyclosporin A
  • ABCC2 protein, human
  • Antiviral Agents
  • Cyclophilin D
  • Cyclosporins
  • Immunosuppressive Agents
  • Liver-Specific Organic Anion Transporter 1
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • Organic Anion Transporters
  • SLCO1B1 protein, human
  • Cyclosporine
  • Cyclophilins
  • alisporivir
Topics
  • Animals
  • Antiviral Agents (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
  • Chemistry Techniques, Synthetic
  • Crystallography, X-Ray
  • Cyclophilin D
  • Cyclophilins (antagonists & inhibitors, chemistry, metabolism)
  • Cyclosporine (chemistry, pharmacology)
  • Cyclosporins (chemistry, pharmacology)
  • Dogs
  • Hepacivirus (drug effects)
  • Hepatitis C (drug therapy)
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Immunosuppressive Agents (chemistry, pharmacology)
  • Liver-Specific Organic Anion Transporter 1
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins (antagonists & inhibitors)
  • Organic Anion Transporters (antagonists & inhibitors)
  • Rats
  • Structure-Activity Relationship
  • Virus Replication (drug effects)

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