Discovery of GLPG2737, a Potent Type 2 Corrector of CFTR for the Treatment of Cystic Fibrosis in Combination with a Potentiator and a Type 1 Co-corrector.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein. This epithelial anion channel regulates the active transport of chloride and bicarbonate ions across membranes. Mutations result in reduced surface expression of CFTR channels with impaired functionality. Correctors are small molecules that support the trafficking of CFTR to increase its membrane expression. Such correctors can have different mechanisms of action. Combinations may result in a further improved therapeutic benefit. We describe the identification and optimization of a new pyrazolol3,4-bl pyridine-6-carboxylic acid series with high potency and efficacy in rescuing CFTR from the cell surface. Investigations showed that carboxylic acid group replacement with acylsulfonamides and acylsulfonylureas improved ADMET and PK properties, leading to the discovery of the structurally novel co-corrector GLPG2737. The addition of GLPG2737 to the combination of the potentiator GLPG1837 and C1 corrector 4 led to an 8-fold increase in the F508del CFTR activity.

Allium sativum@AgNPs and Phyllanthus urinaria@AgNPs: a comparative analysis for antibacterial application.

Although medicinal herbs contain many biologically active ingredients that can act as antibiotic agents, most of them are difficult to dissolve in lipids and absorb through biofilms in the gastrointestinal tract. Besides, silver nanoparticles (AgNPs) have been widely used as a potential antibacterial agent, however, to achieve a bactericidal effect, high concentrations are required. In this work, AgNPs were combined into plant-based antibiotic nanoemulsions using biocompatible alginate/carboxyl methylcellulose scaffolds. The silver nanoparticles were prepared by a green method with an aqueous extract of Allium sativum or Phyllanthus urinaria extract. The botanical antibiotic components in the alcoholic extract of these plants were encapsulated with emulsifier poloxamer 407 to reduce the particle size, and make the active ingredients both water-soluble and lipid-soluble. Field emission scanning electron microscopy (FESEM) and energy-dispersive X-ray (EDX) analysis showed that the prepared nanosystems were spherical with a size of about 20 nm. Fourier transform infrared spectroscopy (FTIR) confirmed the interaction of the extracts and the alginate/carboxyl methylcellulose carrier. In vitro drug release kinetics of allicin and phyllanthin from the nanosystems exhibited a retarded release under different biological pH conditions. The antimicrobial activity of the synthesized nanoformulations were tested against Escherichia coli. The results showed that the nanosystem based on Allium sativum possesses a significantly higher antimicrobial activity against the tested organisms. Therefore, the combination of AgNPs with active compounds from Allium sativum extract is a good candidate for in vivo infection treatment application.

Modification of expanded clay carrier for enhancing the immobilization and nitrogen removal capacity of nitrifying and denitrifying bacteria in the aquaculture system.

In aquaculture systems, the treatment of nitrogen pollution has always been a center of attention due to its impact on productiveness. The bioremediation method based on simultaneous nitrification and denitrification was often used to effectively remove ammonium, nitrite, and nitrate compounds. In addition, the attachment and biofilm formation of the nitrogen-converting bacteria on carriers had superior removal efficiency over the suspended bacteria. Thus, this study focused on the fabrication of a porosity floatable expanded clay (EC) carrier that provided the basic structure for the immobilization of the nitrifiers Nitrosomonas sp., Nitrobacter sp., and the denitrifier Bacillus sp. The EC was also coated with alginate and essential nutrient to support the cohesion and growth of bacteria. Especially, the selected Bacillus sp. previously proved was able to reduce nitrite/nitrate in aerobic conditions. The co-immobilization of these three aerobic bacteria on the prepared carrier would simply the treatment process in practical use. Initial results showed that the integration of essential nutrients (N, P, K) on alginate coated EC (EC_Alg_N) increased bacterial density to (57 ± 3) × 107 - (430 ± 30) × 108 CFU/g, which then led to the enhancement of removal efficiency up to 91.62 ± 0.67% in the medium containing initial nitrogen content of 60 mg-N/L. The nitrogen removal efficacy of bacterial immobilized EC_Alg_N remained at 83.95 ± 0.15% after being reused for 6 cycles. In conclusion, the bacterial immobilized EC_Alg_N could be a potential material for nitrogen polluted wastewater treatment in aquaculture systems.

Discovery of 9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one (GLPG1205), a Unique GPR84 Negative Allosteric Modulator Undergoing Evaluation in a Phase II Clinical Trial.

GPR84 is a medium chain free fatty acid-binding G-protein-coupled receptor associated with inflammatory and fibrotic diseases. As the only reported antagonist of GPR84 (PBI-4050) that displays relatively low potency and selectivity, a clear need exists for an improved modulator. Structural optimization of GPR84 antagonist hit 1, identified through high-throughput screening, led to the identification of potent and selective GPR84 inhibitor GLPG1205 (36). Compared with the initial hit, 36 showed improved potency in a guanosine 5'-O-[γ-thio]triphosphate assay, exhibited metabolic stability, and lacked activity against phosphodiesterase-4. This novel pharmacological tool allowed investigation of the therapeutic potential of GPR84 inhibition. At once-daily doses of 3 and 10 mg/kg, GLPG1205 reduced disease activity index score and neutrophil infiltration in a mouse dextran sodium sulfate-induced chronic inflammatory bowel disease model, with efficacy similar to positive-control compound sulfasalazine. The drug discovery steps leading to GLPG1205 identification, currently under phase II clinical investigation, are described herein.