Current interferon-based therapeutics for hepatitis C virus (HCV) are successful in only 40-50% of patients treated, and while there are candidates in development that inhibit key HCV proteins such as NS3-4A protease and NS5B polymerase, there remains a need to find new agents with novel targets. Cyclosporin A (CsA, 1) is a cyclic undecapeptide isolated from the fungus Tolypocladium inflatum that exhibits anti-HCV activity by binding cyclophilin using residues 9-11 and 1-2, but also causes immunosuppression by binding calcineurin using residues 4-7. The clinical candidate SCY-635 (2) possesses a thioalkylamine sidechain at residue 3 that serves to enhance anti-HCV activity and water solubility, and a ?-hydroxyl at residue 4 to attenuate immunosuppression. Herein, we report the synthesis and SAR of CsA analogs (3) modified at residue 8 as an alternative site to improve anti-HCV activity and water solubility while also minimizing immunosuppression. Within this series we have observed anti-HCV activity <200 nM, and weak immunosuppressive potential.

Synthesis and biological evaluation of [D-lysine]<sup>8</sup>cyclosporin A analogs as potential anti-HCV agents

239th National Meeting (2010)

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