Resorufin butyrate as a soluble and monomeric high-throughput substrate for a triglyceride lipase.

Triglyceride lipases such as lipoprotein lipase, endothelial lipase, and hepatic lipase play key roles in controlling the levels of plasma lipoprotein. Accordingly, small-molecule modulation of these species could alter patient lipid profiles with corresponding health effects. Screening of these enzymes for small-molecule therapeutics has historically involved the use of lipid-based particles to mimic native substrates.

Detection of a minor amorphous phase in crystalline etoricoxib by dynamic mechanical analysis: comparison with Raman spectroscopy and modulated differential scanning calorimetry.

Detection and quantification of the amorphous phase of etoricoxib bulk drug substances, a selective cycloogenase-2 inhibitor used for the treatment of osteoarthritis, rheumatoid arthritis, and dental pain, was carried out using modulated differential scanning calorimetry (MDSC), dynamic mechanical analysis (DMA), and Raman spectroscopy. Detection of amorphous content in pharmaceutical powders by DMA is a special application of dynamic mechanical spectroscopy. DMA was found to be a sensitive technique, able to detect the presence of an amorphous phase in a crystalline phase at concentrations as low as 0.

Difluoroethylamines as an amide isostere in inhibitors of cathepsin K.

The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species.

Investigating the hydrate conversion propensity of different etoricoxib lots.

The physical stability of bulk active pharmaceutical ingredients (API) is of significant scientific and regulatory concern. Carrying out physical stability testing on lots with varying rates of hydrate conversion can potentially lead to erroneous conclusions if these rate differences remain unknown and unstudied. The lot dependency of etoricoxib's rate of hemihydrate conversion was investigated and a quick discriminatory technique was developed to qualitatively assess relatively slow to rapidly converting lots.

Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity.

The lysosomal cysteine protease cathepsin K is a target for osteoporosis therapy. The aryl-piperazine-containing cathepsin K inhibitor CRA-013783/L-006235 (1) displays greater than 4000-fold selectivity against the lysosomal/endosomal antitargets cathepsin B, L, and S. However, 1 and other aryl-piperazine-containing analogues, including balicatib (10), are approximately 10-100-fold more potent in cell-based enzyme occupancy assays than against each purified enzyme.