MEDI 98 |
| HIV protease inhibitors (PIs) are relatively lipophilic molecules, and are poorly soluble in water. Some PIs are not absorbed efficiently from the solid state, and require formulations to solubilize the drug. Consequently, PIs have been associated with high pill counts and large capsules. Water-soluble prodrugs could reduce the pill count for these important therapies. We studied the synthesis, cleavage rates, and oral administration of prodrugs of lopinavir/ritonavir (Kaletra™), and some new HIV PIs. We concluded that phosphate and carboxylic acid esters attached directly to the central hydroxy group of these PI cores had slow cleavage rates. We developed a two-step synthesis to introduce a linker that improved the rate of cleavage, and oxymethylphosphate (OMP) and oxyethylphosphate (OEP) prodrugs provided high levels of aqueous solubility and oral bioavailability. The novel OEP prodrugs released acetaldehyde upon cleavage, instead of formaldehyde, and the new synthetic method may be applicable to other drug classes. |
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Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |