From chemical tools to clinical medicines: nonimmunosuppressive cyclophilin inhibitors derived from the cyclosporin and sanglifehrin scaffolds.

Abstract

The cyclophilins are widely expressed enzymes that catalyze the interconversion of the cis and trans peptide bonds of prolines. The immunosuppressive natural products cyclosporine A and sanglifehrin A inhibit the enzymatic activity of the cyclophilins. Chemical modification of both the cyclosporine and sanglifehrin scaffolds has produced many analogues that inhibit cyclophilins in vitro but have reduced immunosuppressive properties. Three nonimmunosuppressive cyclophilin inhibitors (alisporivir, SCY-635, and NIM811) have demonstrated clinical efficacy for the treatment of hepatitis C infection. Additional candidates are in various stages of preclinical development for the treatment of hepatitis C or myocardial reperfusion injury. Recent publications suggest that cyclophilin inhibitors may have utility for the treatment of diverse viral infections, inflammatory indications, and cancer. In this review, we document the structure-activity relationships of the nonimmunosuppressive cyclosporins and sanglifehrins in clinical and preclinical development. Aspects of the pharmacokinetic behavior and chemical biology of these drug candidates are also described.

• Authors: Zachary K Sweeney, Jiping Fu, Brigitte Wiedmann
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 17 Pg. 7145-59 (Sep 11 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24831536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Cyclosporins
• Enzyme Inhibitors
• Lactones
• Spiro Compounds
• sanglifehrin A
• Cyclosporine
• (melle-4)cyclosporin
• Cyclophilins
• alisporivir
• SCY-635

Topics

• Antiviral Agents (chemistry, metabolism, therapeutic use)
• Chemistry, Pharmaceutical (methods, trends)
• Cyclophilins (antagonists & inhibitors, chemistry, metabolism)
• Cyclosporine (chemistry, metabolism, therapeutic use)
• Cyclosporins (chemistry, metabolism, therapeutic use)
• Enzyme Inhibitors (chemistry, metabolism, therapeutic use)
• Hepacivirus (drug effects, physiology)
• Hepatitis C (drug therapy, virology)
• Host-Pathogen Interactions (drug effects)
• Humans
• Lactones (chemistry)
• Models, Molecular
• Molecular Structure
• Protein Binding
• Protein Structure, Tertiary
• Spiro Compounds (chemistry)
• Structure-Activity Relationship