STRUCTURE-ACTIVITY RELATIONSHIP FOR 2 LIPOXYGENASE INHIBITORS AND THEIR POTENTIAL FOR INDUCING NEPHROTIC SYNDROME

In a study of structure-activity relationship with drug-induced nephro pathy two lipoxygenase inhibitors, the N-hydroxyurea derivative 70C (( E)-N-{3-[3-(4-fluorophenoxy) phenyl]-1-(R,S)-methylprop-2-enyl}-N-hydr oxyurea) and the N-hydroxamic acid analogue 360C ((E)-N-{3-[3-(4-fluor ophenoxy) phenyl]-1-(R,S)-methylprop-2-enyl}-N-hydroxamic acid), were administered to rats. 70C and 360C were dosed to female Wistar rats at 100 mg/ kg po daily for 7 days. Another group of rats was given a sin gle intravenous bolus dose of puromycin aminonucleoside (PAN) at 100 m g/kg. Urine samples were collected from all groups during the study an d plasma samples were collected after 7 days. Kidneys were excised and fixed for examination by electron microscopy. 70C- and PAN-treated gr oups both showed early changes in the glomeruli, in which the visceral cells appeared enlarged and showed varying degrees of foot process lo ss. This foot process loss was associated with decreases in total plas ma protein and albumin and increases in the plasma cholesterol, trigly cerides, creatinine, and urea were recorded. Marked proteinuria was ob served in both the 70C and PAN groups. The foot process loss together with increased proteinuria, hypoalbuminemia, hypercholesterolemia, and lipemia are all characteristic of the human condition, Minimal Change Nephrotic Syndrome. All the biochemical and morphological investigati ons showed that 360C-treated rats were similar to the control group, s uggesting that the hydroxyurea moiety of 70C is responsible, either di rectly or indirectly, for the nephrotic syndrome seen in rats. (C) 199 7 Academic press.