Hepatitis C virus (HCV) is a global health concern; recent estimates suggest that 2.2 to 3% of the world's population, equivalent to 130 to 170 million individuals, are chronically infected with the virus (13, 31). These patients are at risk of developing debilitating liver diseases such as cirrhosis and hepatocellular carcinoma (1). Furthermore, current models suggest that the burden of HCV-associated disease is set to rise for the next 20 years (6). There is no HCV vaccine; the current standard of care (SOC) involves lengthy treatments with ribavirin and injected pegylated interferon, which exhibit variable efficacies and are associated with severe, and sometimes lifethreatening, side effects. Encouragingly, many direct-acting antiviral (DAA) molecules are in clinical development, and the most advanced (telaprevir and boceprevir) will probably be used to treat HCV-infected patients in 2011 (19,29,42,43,61). However, caution should be employed against overoptimism; attrition rates are high during drug development, and the first drugs will be given in combination with, not instead of, the current SOC. Therefore, the continued development of additional treatments is needed, especially since it is widely acknowledged that to limit the emergence of drug-resistant viral variants, effective therapeutic strategies for HCV will consist of multiple DAAs (50).A multitude of screening campaigns has revealed many diverse and interesting chemical compounds capable of specifically inhibiting HCV RNA replication. Many of these compounds target the HCV-encoded nonstructural (NS) proteins (NS3, NS4A, NS4B, NS5A, and NS5B), which are required for HCV genome synthesis (3, 37). To instigate HCV genome replication, the NS proteins interact with viral genomes and certain host-encoded factors to form multiprotein assemblies termed "replication complexes" (RCs), which are sites of viral RNA synthesis derived from the endoplasmic reticulum (ER) (8,14,45,53). In HCV-infected cells, RCs are juxtaposed to intracellular lipid storage organelles termed lipid droplets (LDs), which are coated with the HCV capsid protein (core) and probably serve as platforms to accept replicated genomes from RCs to initiate virion assembly (26,44,53). Of considerable interest are inhibitors that target the HCV-encoded NS5A protein. These inhibitors were originally discovered from the screening of cells containing HCV subgenomic replicons against libraries of small molecules and were identified as NS5A inhibitors by utilizing a strategy termed "chemical genetics" (12, 32). NS5A-targeting inhibitors are notable for their unprecedented potency in cell-based HCV replication assays: 50% inhibitory concentrations (IC 50 s) in the low-picomolar

The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, a member of the melastatin subfamily, is activated by cold temperatures (<28 °C), and antagonists of this channel have the potential to treat cold induced allodynia and hyperalgesia. However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. We report herein the identification and optimization of a series of TRPM8 antagonists that ultimately led to the discovery of PF-05105679. The clinical finding with this compound will be discussed, including both efficacy and its ability to affect thermoregulation processes in humans.

In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl‐linked pyrrolidine NS5A replication complex inhibitors were probed and structure–activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H‐bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second‐generation antiviral agents targeting NS5A.

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.

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