The deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) causes a severe defect in folding and trafficking of the chloride channel resulting in its absence at the plasma membrane of epithelial cells leading to cystic fibrosis. Progress in the understanding of the disease increased over the past decades and led to the awareness that combinations of mechanistically different CFTR modulators are required to obtain meaningful clinical benefit. Today, there remains an unmet need for identification and development of more effective CFTR modulator combinations to improve existing therapies for patients carrying the F508del mutation. Here, we describe the identification of a novel F508del corrector using functional assays. We provide experimental evidence that the clinical candidate GLPG/ABBV-2737 represents a novel class of corrector exerting activity both on its own and in combination with VX809 or GLPG/ABBV-2222.

There is still a high unmet need for the treatment of most patients with cystic fibrosis (CF). The identification and development of new Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators is necessary to achieve higher clinical benefit in patients. In this report we describe the characterization of novel potentiators. From a small screening campaign on F508del CFTR, hits were developed leading to the identification of pre-clinical candidates GLPG1837 and GLPG2451, each derived from a distinct chemical series. Both drug candidates enhance WT CFTR activity as well as low temperature or corrector rescued F508del CFTR, and are able to improve channel activity on a series of Class III, IV CFTR mutants. The observed activities in YFP halide assays translated well to primary cells derived from CF lungs when measured using Trans-epithelial clamp circuit (TECC). Both potentiators improve F508del CFTR channel opening in a similar manner, increasing the open time and reducing the closed time of the channel. When evaluating the potentiators in a chronic setting on corrected F508del CFTR, no reduction of channel activity in presence of potentiator was observed. The current work identifies and characterizes novel CFTR potentiators GLPG1837 and GLPG2451, which may offer new therapeutic options for CF patients.

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A series of human estrogen receptor (hER) mimics were synthesised. On the basis of the knowledge on the structure of the hormone binding domain of the hER, three different peptide chains were constructed onto a tripodal scaffold. By using a fully automated solid-phase synthesis protocol, 120 members with known identity were synthesised in only a week. Affinity towards estrogenic compounds was checked by affinity LC. For this purpose, ethinylestradiol was "clicked" onto a modified-silica phase, and the obtained material was packed into an HPLC column. The results stemming from the affinity LC experiments were confirmed by clicking one library member to silica and by using this solid phase to extract different endocrine-disrupting chemicals (EDCs) from aqueous media

Stationary phases containing pyridine, phenol, aniline and morpholine groups were synthesized using copper (I)-catalyzed azide-alkyne cycloaddition click reactions. The backbone of the stationary phases was aminopropyl silica. The stationary phases were evaluated in packed-column supercritical fluid chromatography (pSFC) with acidic and basic solutes without addition of additives. The analysis of metoclopromide and its impurities by SFC-time-of-flight mass spectrometry (SFC-TOFMS) on the phenol phase is presented. In the click reaction, the 1,2,3-triazole ring is formed and to assess its influence on the polarity/selectivity, the click phases were compared to a commercial available 1,2,4-triazole hydrophilic interaction liquid chromatography (HILIC) phase. The phases were also compared to two extensively used stationary phases in SFC namely 2-ethyl pyridine and bare silica. To allow comparison with other phases used in SFC, linear solvation energy relationships (LSER) of the click phases were determined. Synthesis of stationary phases containing pyridine, phenol, aniline and morpholine via click chemistry and their characterization and evaluation in supercritical fluid chromatography Dunkle M et al. Synthesis of stationary phases containing pyridine, phenol, aniline and morpholine 86 Scientia Chromatographica 2014; 6(2):85-103 Synthesis of stationary phases containing pyridine, phenol, aniline and morpholine Dunkle M et al. Scientia Chromatographica 2014; 6(2):85-103