Design, synthesis, and testing of potential antisickling agents. 6. Rheologic studies with active phenoxy and...

In vitro rheologic studies have been performed with homozygous sickle erythrocytes in the presence of phenoxy and benzyloxy antigelling agents. The results correlate with those obtained previously from a standard hemoglobin S solubility assay (C-sat) that monitors the inhibition of hemoglobin S polymerization in solution. The order of activity of compounds in both studies was found to be about the same. The rheologic assay monitors the reduction in pressure (130 mm Hg sickled vs 9 mm Hg nonsickled) needed to push erythrocytes through a 5 micron filter. Among the drugs studied, the antilipidemic drug Clofibrate reduced the filtration pressure by as little as 9%, and a derivative of the diuretic agent ethacrynic acid (Merck-595, 595) reduced it by as much as 94%. Human Serum Albumin (HSA) (0.1% wt/vol) drastically reduced the activity of the noncovalently-acting aromatic acids by requiring at least three times the concentration of drug to obtain similar reductions in pressure. Two covalently-acting compounds, ethacrynic acid and Merck-595, 595, strongly increased the filterability of homozygous S erythrocytes at 1 and 3 mM drug concentrations even in the presence of HSA. No reason is given for the strong inhibitory effect of HSA at such high drug to HSA concentrations.