Rupendra Simlot

Substituted cyclic imides as potential anti-gout agents

N-substituted cyclic imides of phthalimide, 2,3-dihydrohalazine-1,4-dione, and diphenimide were shown to reduce the serum uric acid levels in normal and hyperuric mice at 20 mg/kg/day I.P. for 14 days. The agents were potent inhibitors of commercial xanthine dehydrogenase and xanthine oxidase enzyme activities with IC50 values from 10(-7) to 10(-8) M concentrations of drug.

Investigation of 3,5-Isoxazolidinediones as Hypolipidemic Agents in Rodents

A series of 2-benzoyl-4,4-dialkyl-3,5-isoxazolidinediones proved to have potent hypolipidemic activity, lowering both serum cholesterol and triglyceride levels at 10 or 20 mg/kg/day, IP and orally in rodents. 2-(3,4,5-Trimethoxybenzoyl)-4,4-diethyl-3,5-isoxazolidinedione (4) afforded the best hypolipidemic activity lowering normolipidemic CFl mouse serum cholesterol levels 49% and serum triglyceride levels 34% at 20 mg/kg/day, IP. Compound 4 was selected as a typical derivative of the chemical class for further detailed studies. Serum cholesterol levels in normolipidemic Sprague Dawley male rats were reduced 45% after 8 weeks at 10 and 20 mg/kg/day of compound, orally. Serum triglyceride levels were reduced 38–49% at 10 and 20 mg/kg/day, orally. In vitro liver enzyme activities studies in normolipidemic CFl mice showed the compound inhibited mitochondrial citrate exchange, acetyl CoA synthetase, HMG CoA reductase, acyl CoA cholesterol acyl transferase, acetyl CoA carboxylase, sn-glycerol-3-phosphate acyl transferase, phosphatidylate phosphohydrolase and heparin-induced lipoprotein lipase activities with increases in the activities of cholesterol ester hydrolase and ATP-dependent citrate lyase. Similar enzyme activities were inhibited in vivo except HMG CoA reductase activity was not inhibited in rat liver or small intestinal mucosa after 8 weeks drug administration. Cholesterol levels were reduced in tissues after 8 weeks administration of compound 4 in normolipidemic rats. Bile cholesterol and triglyceride levels were elevated after two weeks administration to rats at 20 mg/kg/day. Serum lipoprotein levels in normolipidemic and hyperlipidemic rats showed the cholesterol levels in VLDL and LDL fractions after 4, 6 and 8 weeks at 10 and 20 mg/kg/day were reduced whereas HDL-cholesterol levels were significantly elevated. Studies demonstrated that 3H-cholesterol and 14C-palmitic acid incorporation into lipids of the lipoprotein fraction was reduced by the drug but 32P-incorporation was generally elevated. The agent demonstrated no observable toxicity in rats after 8 weeks administration, orally. The acute toxicity study in normolipidemic mice at 20, 40 and 100 mg/ kg/day, IP, demonstrated no observable harmful effects of the drug.

Potential aldose reductase inhibitors: 1,2,4-triazolidine-3,5-diones and 2-(3,4,5-trimethoxybenzoyl)-4,4-diethyl-3,5-isoxazolidinedione .

1,2,4-Triazolidine-3,5-diones and the 3,5-isoxazolidinedione were, observed to be, potent inhibitors of rat lens aldose reductase activity. In vivo in streptozotocin-diabetic rats, selected agents at 20 mg/kg/day, orally for 21 days reduced significantly the sorbitol levels of rbc, lens and sciatic nerves, suggesting that these derivatives may have some usefulness to treat clinical complications of diabetes mellitus.

The Effects of N(4-Methylphenyl)diphenimide on Lipid Metabolism of Sprague Dawley Rats

N(4-Methylphenyl)diphenimide proved to be an effective hypolipidemic agent in rats at 10 and 20 mg/kg/day. Both serum cholesterol and triglyceride levels were reduced significantly. Decreases in tissue lipids as well as VLDL cholesterol levels were observed. HDL-cholesterol was elevated even at 10 mg/kg/day. The agent was equally effective in hyperlipidemic diet-induced rats, lowering serum lipids and VLDL- and LDL-cholesterol while elevating HDL-cholesterol levels. The drug interfered with the incorporation of 3H-cholesterol and 3H-palmitic acid into chylomicrons, VLDL, and LDL. The two precursors were incorporated at a higher rate into HDL.3H-Leucine was incorporated into chylomicrons, VLDL, and LDL at a higher rate, but not into HDL. Reduced uptake of the precursor for lipid synthesis was noted in tissues after treatment with the drug.

DISPOSITION OF THE HYPOLIPIDAEMIC AGENT, 6-AMINO-2-MERCAPTO-5-METHYLPYRIMIDINE-4-CARBOXYLIC ACID, IN SPRAGUE-DAWLEY RATS

Abstract— The disposition of [2‐14C] 6‐amino‐2‐mercapto‐5‐methyl‐pyrimidine‐4‐carboxylic acid has been determined in rats following intravenous and oral administration. A two‐compartment pharmacokinetic model fitted to the blood and urinary data predicted its maximum terminal (β) half‐life to be 38 h. Urinary and faecal excretion accounted for approximately 30 and 8% of the administered radioactivity, respectively. The parent compound accounted for 88% of the urine radioactivity after oral administration. In a tissue distribution study, the largest percentages of radioactivity were found in the skin and carcass; by 24 h, all other organs contained less than 1% of the administered radioactivity. The drug was highly water soluble, not extensively bound to plasma proteins, nor taken up by red blood cells. The drug uptake by human fibroblasts or rat aorta cells appeared to be by passive diffusion.