Design and Synthesis of Ethyl Pyrrolidine‐5,5‐trans‐lactams as Inhibitors of Hepatitis C Virus NS3/4A Protease.

Abstract

Fused pyrrole derivativesFused pyrrole derivatives R 0160 Design and Synthesis of Ethyl Pyrrolidine-5,5-trans-lactams as Inhibitors of Hepatitis C Virus NS3/4A Protease. -Starting from (IV) the diastereomeric series of (IX) is also prepared. Compound (IXa) shows an IC 50 of 30 µM (no yields given). -(SLATER*, M. J.; et al.; Bioorg. Med. Chem. Lett. 12 (2002) 23, 3359-3362; Glaxo Wellcome Med. Res. Cent., Stevenage, Hertfordshire SG1 2NY, UK; Eng.) -K. Schneider 12-113

Hepatitis C Virus Therapies: Current Treatments, Targets and Future Perspectives

“…Unfortunately, these compounds were mostly nonselective and inhibited the activity of host serine proteases such as chymotrypsin, trypsin and elastase, in addition to the desired HCV protease target. Compounds GW-3112, GW-2549 and GW-0569 exhibit IC 50 values of 0.45, 0.78 and 9 µM, respectively, in the replicon ELISA assay, and <0.7, 0.75 and 10.6 µM, respectively, in the vaccinia ELISA (a recombinant vaccinia virus drives expression of the HCV NS3-5 polyprotein and detection of cleaved products occurs in the absence of specific protease inhibitors) (Parry et al, 2002;Slater et al, 2002). A series of pyrrolidine-5,5-trans lactams is in preclinical development by GlaxoSmithKline (Middlesex, UK) ( Figure 3c).…”

“…Although the NS4A co-factor and NS3 helicase domain do not bind in the protease active site, evidence indicates that these factors can affect protease conformation, resulting Peptidic inhibitors: carboxylic acid hexapeptide inhibitor and its antiviral activity (a) (Narjes et al, 2000); and Boehringer Ingelheim inhibitor, BILN 2061 and its antiviral activity (b) (Benhamou et al, 2002;Hinrichsen et al, 2002). Non-peptidic inhibitors: one of a series of pyrrolidine-5,5-trans-lactams from GlaxoSmithKline (c) (Parry et al, 2002;Slater et al, 2002). SAR-derived tris-phosphonoalanine analogue of Hit 1.…”

“…A series of pyrrolidine-5,5-trans lactams is in preclinical development by GlaxoSmithKline (Middlesex, UK) ( Figure 3c). Compounds GW-3112, GW-2549 and GW-0569 exhibit IC 50 values of 0.45, 0.78 and 9 µM, respectively, in the replicon ELISA assay, and <0.7, 0.75 and 10.6 µM, respectively, in the vaccinia ELISA (a recombinant vaccinia virus drives expression of the HCV NS3-5 polyprotein and detection of cleaved products occurs in the absence of specific protease inhibitors) (Parry et al, 2002;Slater et al, 2002). Interestingly, the compounds are also active against the surrogate GBV-B.…”