THERAPY FOR UROLITHIASIS BY HYDROXAMIC ACIDS. III. UREASE INHIBITORY POTENCY AND URINARY EXCRETION RATE OF N-ACYLGLYCINOHYDROXAMIC ACIDS

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Hydroxamic acid, a potent urease inhibitor, having a high urinary excretion rate is expected to be a therapeutic agent for urolithiasis caused by urea-splitting bacterial infection of the urinary tract. Twenty-one new derivatives of N-aliphatic-acylglycinohydroxamic acids (GHAs) were synthesized, and their inhibitory potencies against the urease activity of sword bean in a phosphate buffer and against the ureolytic activity of Proteus mirabilis in human urine, and their urinary excretion rates in rats were also measured for this purpose. I_<50> values of most of GHAs against the urease activity of sword bean were about 1 to 10 μM and 2-ethyl-n-butyroyl GHA was the most potent inhibitor with the value of 0.79 μM. I_<50> values of most of the GHAs against the ureolytic activity of Proteus mirabilis were about 5 to 50 μM and n-nonaroyl GHA was the most potent inhibitor with the value of 3.6 μM. 2,2-Dimethylpropionyl GHA had the highest urinary excretion rate with the recovery of 11%. Routes of administration of 2,2-dimethylpropionyl GHA and sex of rats used did not affect the amount of urinary excretion at all. The results in this report suggest that DL 2-methyl-n-butyroyl, 2-ethyl-n-butyroyl and 2,2-dimethylpropionyl GHA are the most hopeful therapeutic agents for urolithiasis among them.