The O-methyl analogue of zanamivir is claimed to protect mice against a lethal influenza infection following oral administration of the prodrug 47 whilst the bicyclic ether 48 is the first zanamivir derivative to demonstrate oral efficacy in the mouse model (127,128). The optimization of a screening lead into potent, cyclopentane-based inhibitors of neuraminidase using a combination of structure-based design and combinatorial chemistry has been described in detail (129).
The thioamide 49 was the most potent of a series of influenza fusion inhibitors whilst the tetramic acid 50 was the most potent of a new class of influenza endonuclease inhibitors, IC5o = 6.6 ^M (130,131).
Inhibitors of Human Rhinovirus (HRV) - The NDA for the HRV uncoating inhibitor pleconaril (Picovir™) was rejected by the FDA on May 31st with the agency requesting additional drug interactions studies.
Mechanism-based inhibitors of the HRV 3C cysteine protease have been probed using a combination of structure-based design principles and parallel synthesis methods in an effort to find less peptidic inhibitors (132). The chroman 51 emerged as an inhibitor of HRV-14 replication in cell culture, EC5o = 160 nM; however, the serotype coverage of this compound was poor with much reduced potency against other subtypes, an observation rationalized in the context of structural data (132). The HRV 2A cysteine protease releases itself from the viral P2 polyprotein, cleaves the P2 in both a c/s and trans fashion to release the 2B and 2C proteins and also proteolyzes the host cap binding complex in order to compromise host cell transcription. A series of W-phenyiated pyrazole derivatives have been claimed as inhibitors of this essential enzyme with 52 an effective antiviral agent in cell culture, EC5o = 1 8 |iM, CC5o = 388 liM (133). The HRV RNA-dependent RNA polymerase from HRV-16, a potential drug discovery target, has been cloned, expressed and purified from E. coli and shown to be enzymatically active (134).
Was this article helpful?