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A diglyceride derivative of a pentapeptide renin inhibitor, the 1,3-dipalmitoyl-[Iva-Phe-Nle-Sta-Ala-Sta-acetyl]-glycerol was synthesized and tested in vitro as a potential prodrug for oral administration. The ability of the diglyceride analog to inhibit the renin activity was equivalent to that of the parent peptide after predigestion with pancreatic lipase. Furthermore, the presence of the palmitoyl groups was found to induce, in vitro, an efficient protection of the peptide from gastric and intestinal hydrolysis. During incubation with intestinal and gastric fluids, and with alpha-chymotrypsin and pancreatic lipase, the glycerolipidic derivative was more stable than the peptide alone. These results support the use of glycerolipidic prodrug for oral administration of peptides.

A new strategy is presented to develop macrofilaricidal compounds orally administered and able to concentrate in the lymphatic system. A diglyceride derivative of melphalan, 1,3-dipalmitoyl-2-(4'(bis(2''-chloroethyl)amino)phenylalaninoyl)gl y cerol, was synthesized. The esterification of melphalan by 1,3-dipalmitin allowed chemical stabilization of the alkylating agent in aqueous dispersion. No degradation of this prodrug was observed after a 3-month storage of an aqueous dispersion at 4 degrees C. The filaricidal activity of the prodrug was compared with those of melphalan in vitro against adults, infective larvae and microfilariae of Molinema dessetae, and evaluated in vivo on Molinema dessetae infected Proechimy oris. In vitro, melphalan and the glycerolipidic prodrug were inactive against microfilariae but active at 1 mmol/l against infective larvae and adults. In vivo studies were performed with rodents subcutaneously inoculated with infective larvae from Aedes aegypti. The number of macrofilariae was significantly reduced following treatment with a single oral dose of the alkylating agent prodrug (0.082 mmol/kg).