ABSTRACT
Phosphate binders are used for the treatment of hyperphosphatemia in hemodialysis patients with chronic kidney disease. Sevelamer, a phosphate-binding polymer, has been reported to bind bile acids or fatty acids and thereby decrease its phosphate-binding capacity. The novel phosphate binder TRK-390 is a poly (allylamine) polymer that has been shown to have enhanced phosphate selectivity, with low bile-acid-binding. In this study we evaluated the effect of fatty acids on the phosphate-binding capacity of TRK-390. In the absence of fatty acids and bile acids, the phosphate-binding capacity of TRK-390 was similar to that of sevelamer. In the presence of fatty acids and bile acids, the phosphate-binding capacity of TRK-390 was reduced to 83%; in contrast, that of sevelamer was reduced to 35%. TRK-390 and sevelamer showed a similar effect in lowering urinary phosphate excretion in normal rats fed a normal diet. However, urinary phosphate excretion of rats treated with TRK-390 was reduced by about one half of that obtained with sevelamer, when given with a high-fat diet that had a fat content similar to the diet of hemodialysis patients. TRK-390 was superior in terms of phosphate selectivity in the presence of fatty acids and bile acids in vitro, and the phosphate-binding capacity of TRK-390 in vivo was shown to be less affected by fat in comparison with that of sevelamer. Thus, TRK-390 is expected to be useful as a novel highly selective phosphate binder.
Subject(s)
Allyl Compounds/metabolism , Fatty Acids/pharmacology , Phosphates/metabolism , Polyamines/metabolism , Polymers/metabolism , Animals , Bile Acids and Salts/metabolism , Diet, High-Fat/adverse effects , Feces , Humans , Male , Oleic Acid/pharmacology , Phosphates/urine , Rats , Rats, Sprague-Dawley , Substrate Specificity , Taurocholic Acid/pharmacologyABSTRACT
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.
Subject(s)
Drug Design , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemistry , Urea/analogs & derivatives , Administration, Oral , Animals , Binding Sites , Crystallography, X-Ray , Cytochrome P-450 Enzyme System/metabolism , Drug Evaluation, Preclinical , Humans , Imidazoles/chemistry , Imidazoles/metabolism , Lipopolysaccharides/toxicity , Liver/drug effects , Liver/metabolism , Mice , Mitogen-Activated Protein Kinase 14/metabolism , Naphthalenes/chemistry , Naphthalenes/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/toxicity , Protein Structure, Tertiary , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyridines/chemistry , Pyridines/metabolism , Tumor Necrosis Factor-alpha/blood , Urea/chemical synthesis , Urea/toxicityABSTRACT
We report the discovery and structure-activity relationship of 2,6-disubstituted pyrazines, which are potent and selective CK2 inhibitors. Lead compound 1 was identified, and derivatives were prepared to develop potent inhibitory activity. As a result, we obtained compound 7, which was the smallest unit that retained potency. Then, introducing an aminoalkyl group at the 6-position of the indazole ring resulted in improved efficacy in both enzymatic and cell-based CK2 inhibition assays. Moreover, compound 13 showed selectivity against other kinases and in vivo efficacy in a rat nephritis model. These results show that 2,6-disubstituted pyrazines have potential as therapeutic agents for nephritis.
