The metabolic syndrome is a strong predictor of nonalcoholic fatty liver disease.

Ramatroban (Baynas, BAY u3405), a thromboxane A 2 (TxA 2 ) antagonist marketed for allergic rhinitis, has been shown to partially attenuate prostaglandin (PG)D 2 -induced bronchial hyperresponsiveness in humans, as well as reduce antigen-induced early-and late-phase inflammatory responses in mice, guinea pigs, and rats. PGD 2 is known to induce eosinophilia following intranasal administration, and to induce eosinophil activation in vitro. In addition to the TxA 2 receptor, PGD 2 is known as a ligand for the PGD 2 receptor, and the newly identified G-protein-coupled chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). To fully characterize PGD 2 -mediated inflammatory responses relevant to eosinophil activation, further analysis of the mechanism of action of ramatroban has now been performed. PGD 2 -stimulated human eosinophil migration was shown to be mediated exclusively through activation of CRTH2, and surprisingly, these effects were completely inhibited by ramatroban. This is also the first report detailing an orally bioavailable small molecule CRTH2 antagonist. Our findings suggest that clinical efficacy of ramatroban may be in part mediated through its action on this Th2-, eosinophil-, and basophil-specific chemoattractant receptor.

Human R-1,3-fucosyltransferase V (FucT V), which catalyzes the transfer of L-fucose moiety from guanosine diphosphate -L-fucose (GDP-Fuc) to an acceptor sugar to form sialyl Lewis x (sLe x ), was shown to proceed through an ordered, sequential mechanism by product inhibition studies. The designed azatrisaccharide propyl 2-acetamido- (2), prepared by covalently linking the N-group of -L-homofuconojirimycin (1) to the 3-OH of LacNAc through an ethylene unit, in the presence of GDP was found to be an effective inhibitor of FucT V. In the presence of 30 µM GDP, the concentration of 2 necessary to cause 50% inhibition was reduced 77-fold to 31 µM. Presumably, the azatrisaccharide and GDP form a complex which mimics the transition state of the enzymatic reaction. Given the low affinity of FucT V for its substrate LacNAc (K m ) 35 mM), the designed azatrisaccharide in the presence of GDP represents the most potent synergistic inhibitor complex reported so far.

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