HCV inhibitor

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

HBV, hepatitis B HCV, hepatitis C IAP, inhibitor of apoptosis protein DBM, IAP binding motifs INCA, inhibitory CARD NASH, non-alcoholic steatohepatitis PCD, programmed cell death PCI, pan-caspase inhibitor OA, osteoarthritis RA, rheumatoid arthritis Smac, second mitochondria-derived activator of caspases TRAIL, tumor necrosis factor-related apoptosis-inducing ligand. 

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In analogy with the designation of NRTIs and NNRTls for the nucleoside and nonnucleoside type of reverse transcriptase (RT) inhibitors to target HIV, the corresponding inhibitors to target HCV may be termed NRRIs (for nucleoside RNA replicase inhibitors) and NNRRIs (for nonnucleoside RNA replicase inhibitors). 

PSI-6130, upon phosphorylation to its 5 -triphosphate, is incorporated (as PSl-6130-MP) as a nonobligate chain terminator (Murakami et al. 2008) into RNA catalyzed by purified RNA-dependent RNA polymerase (NS5B). PSl-6130 is metabolized intracellularly to the 5 -triphosphate of p-D-2 -deoxy-2 -fluoro-2 -C-methyluridine (PSI-6206) (Ma et al. 2007), but, as compared to the 5 -triphosphate of PSI-6130, the 5 -triphosphate of PSI-6206 is less efficient an inhibitor of HCV RNA-dependent RNA polymerase than PSI-6130 5 -triphosphate (Murakami et al. 2007). 

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