New potent biaryl sulfate-based hepatitis C virus inhibitors.

The discovery of a new series of potent hepatitis C virus (HCV) NS5A inhibitors containing biaryl sulfone or sulfate cores is reported. Structure-activity relationship (SAR) studies on inhibitors containing various substitution patterns of the sulfate or sulfone core structure established that m-,m'- substituted biaryl sulfate core-based inhibitors containing an amide moiety (compound 20) or an imidazole moiety (compound 24) showed extremely high potency. Compound 20 demonstrated double-digit pM potencies against both genotype 1b (GT-1b) and 2a (GT-2a).

Liquid crystal nanoparticle formulation as an oral drug delivery system for liver-specific distribution.

Liquid crystal nanoparticles have been utilized as an efficient tool for drug delivery with enhanced bioavailability, drug stability, and targeted drug delivery. However, the high energy requirements and the high cost of the liquid crystal preparation have been obstacles to their widespread use in the pharmaceutical industry. In this study, we prepared liquid crystal nanoparticles using a phase-inversion temperature method, which is a uniquely low energy process.

Novel benzidine and diaminofluorene prolinamide derivatives as potent hepatitis C virus NS5A inhibitors.

Our study describes the discovery of a series of highly potent hepatitis C virus (HCV) NS5A inhibitors based on symmetrical prolinamide derivatives of benzidine and diaminofluorene. Through modification of benzidine, l-proline, and diaminofluorene derivatives, we developed novel inhibitor structures, which allowed us to establish a library of potent HCV NS5A inhibitors. After optimizing the benzidine prolinamide backbone, we identified inhibitors embedding meta-substituted benzidine core structures that exhibited the most potent anti-HCV activities.

Synthesis toward CRHR1 Antagonists through 2,7-Dimethylpyrazolo[1,5-α][1,3,5]triazin-4(3H)-one C-H Arylation.

A novel synthetic protocol for 8-aryl substituted pyrazolo[1,5-α][1,3,5]triazin-4(3H)-ones was developed employing Pd-catalyzed C-H arylation. The reaction yield was influenced by the presence of a phosphine ligand, pivalic acid, and base selection. With the use of 5-10 mol % catalyst, reactions of 2 with p- or m-substituted aryl bromides proceeded in moderate to good yields.

Potent Hepatitis C Virus NS5A Inhibitors Containing a Benzidine Core.

Here we report the discovery of a series of potent hepatitis C virus (HCV) NS5A inhibitors based on the benzidine prolinamide backbone. Taking a simple synthetic route, we developed a novel inhibitor structure, which allows easy modification, and through optimization of the capping group, we identified compound 6 with highly potent anti-HCV activity. Compound 6 is nontoxic and is anticipated to be an effective HCV drug candidate.