Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis.

With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL-23-induced mouse skin inflammation model.

Removal of ciprofloxacin in simulated digestive media by activated charcoal entrapped within zinc-pectinate beads.

Beads made of a zinc-pectinate matrix containing activated charcoal were designed for the adsorption of colonic residual antibiotics responsible of the emergence of resistance. Bead stability was shown to correlate with bead zinc content, 0.08 mg/mg being the minimal amount of zinc that protects the egg-box structure against total disintegration. Moreover, the stability in simulated gastro-intestinal media was shown to be related to the composition of the incubation medium. Indeed, gastric medium was shown to extract a large amount of zinc inducing an early disintegration of the beads in the intestinal medium, making necessary their protection by gastro-resistant capsules. Simulated intestinal medium buffered by phosphate was not adapted for the disintegration studies since the formation of a zinc phosphate precipitate on beads surface enhances their resistance to further degradation by pectinases contained in colonic medium. On the other hand, beads incubated in HEPES were stable in intestinal medium and nicely degraded by pectinases contained in simulated colonic medium. Despite this stability, coating with Eudragit RS was needed to prevent the early adsorption of antibiotics in intestinal medium. Adsorption studies in the simulated colonic medium show that the adsorption capacity of activated charcoal is not modified after its encapsulation within pectin beads making the elimination of ciprofloxacin reaching the colon clinically feasible.

Extracorporeal adsorption of anti-factor VIII allo-antibodies on randomly functionalized polystyrene resins.

The occurrence of anti-factor VIII (FVIII) allo-antibodies is a severe complication of the treatment of haemophilia A patients, leading to the inhibition of transfused FVIII activity. The effective elimination of these inhibitory antibodies plays a decisive role in the management of affected patients. To achieve this, immunoadsorption devices employing synthetic adsorbers, which selectively eliminate inhibitors, are of interest in the treatment strategy of haemophilia A patients with inhibitors. Adsorbers consisting of polystyrene-based beads substituted with sulphonate and L-tyrosyl methylester groups, which mimic part of epitope of FVIII molecule recognized by inhibitors, exhibit selective binding capacities towards anti-FVIII antibodies. The adsorption of FVIII inhibitors was investigated by simulating an extracorporeal circulation of haemophilic plasma over these functionalized resins. These innovative adsorbers are able to remove around 25% of anti-FVIII antibodies in 15 minutes depending on the plasma tested. Furthermore, they do not modify the amount of essential plasmatic proteins or residual immunoglobulins G. Experiments which were carried out using different plasmas with various inhibitor titres demonstrate a good reproducibility regarding the adsorption capacity of the synthetic resin. The characteristics of adsorption are similar on either native or regenerated resins. Both the purely synthetic nature of the resin and its easy processability demonstrate the real advantages over currently available protocols. This synthetic adsorber is a major technological advance in selective removal of FVIII inhibitory antibodies.