Background: CCR2 plays a key role in regulating monocyte trafficking to sites of inflammation and therefore has been the focus of much interest as a target for inflammatory disease.

No abstract

Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 μM) and cell-based replicon (EC(50) = 0.02 μM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 μM·h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.

No abstract

[reaction: see text]n-Pentenyl ortho esters (NPOEs) and n-pentenyl glycosides (NPGs) are interconvertible glycosyl donors which are activated by reaction with halonium ions. In a series of cyclic syn-1,3-diols, NPOEs have been found to specifically glycosylate the equatorial-OH while the NPG glycosylates predominantly, but not exclusively, the axial-OH. When the cyclic diol acceptor is presented with equivalent amounts of an NPOE and an NPG in a three-component-reaction, a single, double-glycosylation product is obtained, which conforms to the foregoing preferences, presenting evidence for site-selective glycosylation.