Hiroyuki Meguro

Design and synthesis of novel p38α MAP kinase inhibitors: discovery of pyrazole-benzyl ureas bearing 2-molpholinopyrimidine moiety.

The discovery that pyrazole-benzyl urea derivatives bearing a 2-molpholinopyrimidine moiety are novel p38α inhibitors is described. A comparative view of the binding modes of SB-203580 and BIRB-796 by structural alignment of two X-ray co-crystal structures was utilized to identify this novel series. Modification of the benzyl group led to compound 2b, a highly potent p38α inhibitor. In in vivo studies, 2b inhibited the production of tumor necrosis factor-alpha in lipopolysaccharide-treated mouse in a dose-dependent manner. Furthermore, the results of a 5-day repeated oral dose toxicity study suggest that 2b has low hepatotoxicity.

Biocompatibility of Polysulfone Hemodialysis Membranes and Its Mechanisms: Involvement of Fibrinogen and Its Integrin Receptors in Activation of Platelets and Neutrophils

Abstract Activation of blood cells during hemodialysis is considered to be a significant determinant of biocompatibility of the hemodialysis membrane because it may affect patient health adversely through microvascular inflammation and oxidative stress. This study found very different cell activation among various polysulfone (PSf) hemodialysis membranes. For example, CX‐U, a conventional PSf membrane, induced marked adhesion of platelets to its surface and increased surface expression of activated CD11b and production of reactive oxygen species (ROS) by neutrophils; while NV‐U, a hydrophilic polymer‐immobilized PSf membrane, caused little platelet adhesion and slight CD11b expression and ROS production by neutrophils. Analysis of the molecular mechanisms of the above phenomena on CX‐U and NV‐U indicated that anti‐integrin GPIIb/IIIa antibody blocked platelet adhesion, and that the combination of anti‐CD11b (integrin α subunit of Mac‐1) and anti‐integrin αvβ3 antibodies blocked ROS production by neutrophils. Plasma‐derived fibrinogen, a major ligand of GPIIb/IIIa, Mac‐1, and αvβ3 on membranes, was thus analyzed and found to be more adsorbed to CX‐U than to NV‐U. Moreover, comparison between five PSf membranes showed that the number of adherent platelets and neutrophil ROS production increased with increasing fibrinogen adsorption. These results suggested that fibrinogen, adsorbed on membranes, induced GPIIb/IIIa‐mediated platelet activation and Mac‐1/αvβ3‐mediated neutrophil activation, depending on the amount of adsorption. In conclusion, the use of biocompatible membranes like NV‐U, which show lower adsorption of fibrinogen, is expected to reduce hemodialysis‐induced inflammation and oxidative stress by minimizing cell activation.