Reduction in glucose levels in STZ diabetic rats by 4-(2,2-dimethyl-1-oxopropyl)benzoic acid: A prodrug approach for targeting the liver

The overproduction of glucose by the liver in NIDDM patients markedly contr ibutes to their fasting hyperglycemia and is a direct consequence of the in creased oxidation of excess free fatty acids (FFA) being released from the adipocyte. 2-(1,1-Dimethylethyl)-2-(4-methylphenyl)[1,3]dioxolane (SAH51-64 1, 1) has previously been demonstrated to reduce glucose levels in animal m odels of diabetes by reducing fatty acid oxidation and hence depriving the system of the energy and cofactors necessary for gluconeogenesis. However, attempts at lowering glucose levels in vivo with 1 have been associated wit h toxicity in other organs such as the testes. An approach was developed ut ilizing the natural processing of triglyceride-like intermediates as a basi s for selectively targeting the absorption, processing, and delivery of a p rodrug to the liver. Compounds were identified by this method which lowered glucose levels in vivo without releasing toxic amounts of the active metab olites of 1 into circulation.