Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S), has an IC 50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.

With the quick development of the high-speed railway and the service of the China Railway High-speed (CRH) series for almost a decade, one of the greatest challenges is the management/maintenance of these trains in environmental conditions. It is critical to estimate pitting damage initiation and accumulation and set up a corresponding database in order to support the foundations for interactive corrosion risk management. In this work, the pitting corrosion of a nature-aged commercial 6005A-T6 aluminum extrusion profile for 200 days was studied comprehensively. The heterogeneous microstructures were conventionally identified by the in situ eddy current, suggesting which investigated regions to fabricate samples for. After constant immersion for 240 h in 3.5 wt % NaCl, the shapes and depths of the pits were captured and measured by optical microscope (OM) and three-dimensional optical profilometry (OP), providing detailed quantification of uniform pitting corrosion. The typical features of the pits dominated by the distribution of precipitates include the peripheral dissolution of the Al matrix, channeling corrosion, intergranular attack, and large pits in the grains. Due to the high density of continuous anodic and cathodic particles constituted by alloying elements in coarse grains, the number of pits in the coarse grains was the highest while the number in the fine grains was the lowest, indicating that fine grains have the best corrosion resistance. The experimental dataset of the pit depth integrated with its corresponding microstructure would set the benchmark for further modeling of the pit depth and the remaining ductility, in order to manage the damage tolerance of the materials.

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