title: The Hypolipidemic Activity of a Series of 2,3-Dihydrophthalazine-l,4-dione Derivatives in Rodents.
abstract: A series of substituted 2,3-dihydrophthalazine-l,4-dione derivatives as well as the corresponding N,N-diaminophthalamides were prepared and were demonstrated to have potent hypolipidemic activity, lowering both serum triglyceride and cholesterol levels significantly at 20 mg/kg/day after 16 days of dosing in CF1 male mice. The parent compound, 2,3-dihydrophthalazine-l,4-dione, lowered serum cholesterol 51% and serum triglyceride 43%. 2-(2-Carboxyethyl)-2,3-dihydrophthalazine-l,4-dione demonstrated the best hypocholesterolemic activity, with a 66% reduction after 16 days. The 2-(p-chlorophenyl) derivative demonstrated good activity (>40% reduction) in both screens, as did the 6-methyl-2,3-dihydrophthalazine-l,4-dione derivative. Of the amides, 4-methyk N,N-diaminophthalamide demonstrated the best hypolipidemic activity, affording a greater than 40% reduction. 2,3-Dihydrophthalazine-l,4-dione was found to inhibit the enzyme activity of acetyl CoA synthetase, ATP-dependent citrate lyase, sn-glycerol-3-phosphate acyl transferase, phosphatidylate phosphohydrolase, and mitochondrial citrate exchange of liver. In mice after 16 days of dosing, there was a reduction of cholesterol, triglycerides, neutral lipids, and phospholipids in the liver. Cholesterol and neutral lipids were reduced in rat chylomicrons, very low-density lipoproteins, and low-density lipoproteins. The cholesterol content of the high-density lipoprotein fraction was slightly elevated, but reductions in the triglycerides and phospholipids were observed in this lipoprotein fraction. (3)H-Cholesterol distribution studies showed a lower concentration in the major organs and plasma, with a higher (3)H-cholesterol content in the stomach and large intestine.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, The University of North Carolina, Chapel Hill, North Carolina, 27514.
authors.forename: A R
authors.initials: AR
authors.lastname: Murthy
authors.forename: I H
authors.initials: IH
authors.lastname: Hall
authors.forename: J M
authors.initials: JM
authors.lastname: Chapman
authors.forename: K A
authors.initials: KA
authors.lastname: Rhyne
authors.forename: S D
authors.initials: SD
authors.lastname: Wyrick