LIQUID-CHROMATOGRAPHIC MEASUREMENT OF HYDROPHOBICITY CONSTANTS FOR N-ARYLSULFONYLGLYCINE ALDOSE REDUCTASE INHIBITORS

The hydrophobicity constants for a series of aldose reductase inhibitors (ARIs) are determined by reversed-phase liquid chromatography. A series of reference compounds consisting of 23 barbituric acid derivatives are separated on two phenylsilica stationary phases over a range of methanol concentrations (30-80%) in 0.05 M phosphate buffer. Linear regression analysis of the measured log k' data is used to estimate the capacity factor in 100% water (log k'(w)) for each compound. The log k'(w) values are regressed against the shake-flask-measured 1-octanol-water partition coefficients, producing a correlation of 0.953. the same procedure is then used to estimate the log k'(w) values for a large group of ARIs and their log P values, calculated from the established relationship between log k'(w) and log P from the reference compounds. An initial analysis of the aldose reductase inhibitory activity of these compounds as a function of hydrophobicity alone fails to reveal a clear relationship, demonstrating the need for a multivariant approach for quantitative structure-activity analysis in this series of compounds.; The hydrophobicity constants for a series of aldose reductase inhibitors (ARIs) are determined by reversed-phase liquid chromatography. A series of reference compounds consisting of 23 barbituric acid derivatives are separated on two phenylsilica stationary phases over a range of methanol concentrations (30-80%) in 0.05 M phosphate buffer. Linear regression analysis of the measured log k′ data is used to estimate the capacity factor in 100% water (log k′w) for each compound. The log k′w values are regressed against the shake-flask-measured 1-octanol-water partition coefficients, producing a correlation of 0.953.