title: SCY-635, a novel nonimmunosuppressive analog of cyclosporine that exhibits potent inhibition of hepatitis C virus RNA replication in vitro.
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.
authors.affiliation: Scynexis, Inc., 3501C Tricenter Boulevard, Durham, NC 27713, USA. Sam.Hopkins@scynexis.com
authors.forename: Sam
authors.initials: S
authors.lastname: Hopkins
authors.forename: Bernard
authors.initials: B
authors.lastname: Scorneaux
authors.forename: Zhuhui
authors.initials: Z
authors.lastname: Huang
authors.forename: Michael G
authors.initials: MG
authors.lastname: Murray
authors.forename: Stephen
authors.initials: S
authors.lastname: Wring
authors.forename: Craig
authors.initials: C
authors.lastname: Smitley
authors.forename: Richard
authors.initials: R
authors.lastname: Harris
authors.forename: Frank
authors.initials: F
authors.lastname: Erdmann
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
authors.forename: Yves
authors.initials: Y
authors.lastname: Ribeill
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D021984:Cyclophilin A / Q000378:metabolism; D003524:Cyclosporins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry*; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D012367:RNA, Viral / Q000235:genetics*; D051381:Rats; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D012367:RNA, Viral; D021984:Cyclophilin A; C544142:SCY-635