SCY-635, a novel nonimmunosuppressive analog of cyclosporine that exhibits potent inhibition of hepatitis C virus RNA replication in vitro.

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Hopkins S, Scorneaux B, Huang Z, Murray MG, Wring S, Smitley C, Harris R, Erdmann F, Fischer G, Ribeill Y

SCY-635, a novel nonimmunosuppressive analog of cyclosporine that exhibits potent inhibition of hepatitis C virus RNA replication in vitro.

Antimicrob Agents Chemother. 2010 Feb;54(2):660-72. doi: 10.1128/AAC.00660-09. Epub 2009 Nov 23.

PubMed ID
19933795 [ View in PubMed
]
Abstract

SCY-635 is a novel nonimmunosuppressive cyclosporine-based analog that exhibits potent suppression of hepatitis C virus (HCV) replication in vitro. SCY-635 inhibited the peptidyl prolyl isomerase activity of cyclophilin A at nanomolar concentrations but showed no detectable inhibition of calcineurin phosphatase activity at concentrations up to 2 microM. Metabolic studies indicated that SCY-635 did not induce the major cytochrome P450 enzymes 1A2, 2B6, and 3A4. SCY-635 was a weak inhibitor and a poor substrate for P-glycoprotein. Functional assays with stimulated Jurkat cells and stimulated human peripheral blood mononuclear cells indicated that SCY-635 is a weaker inhibitor of interleukin-2 secretion than cyclosporine. A series of two-drug combination studies was performed in vitro. SCY-635 exhibited synergistic antiviral activity with alpha interferon 2b and additive antiviral activity with ribavirin. SCY-635 was shown to be orally bioavailable in multiple animal species and produced blood and liver concentrations of parent drug that exceeded the 50% effective dose determined in the bicistronic con1b-derived replicon assay. These results suggest that SCY-635 warrants further investigation as a novel therapeutic agent for the treatment of individuals who are chronically infected with HCV.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CyclosporineCytochrome P450 2C19IC 50 (nM)7000N/AN/ADetails
CyclosporineCytochrome P450 2D6IC 50 (nM)>100000N/AN/ADetails
CyclosporineCytochrome P450 3A4IC 50 (nM)6600N/AN/ADetails
CyclosporinePeptidyl-prolyl cis-trans isomerase AKi (nM)2.64N/AN/ADetails