Water-Soluble Prodrugs of the Human Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir

Abstract

We studied the synthesis, cleavage rates, and oral administration of prodrugs of the HIV protease inhibitors (PIs) lopinavir and ritonavir. Phosphate esters attached directly to the central hydroxyl groups of these PIs did not demonstrate enzyme-mediated cleavage in vitro and did not provide measurable plasma levels of the parent drugs in vivo. However, oxymethylphosphate (OMP) and oxyethylphosphate (OEP) prodrugs provided improved rates of cleavage, high levels of aqueous solubility, and high plasma levels of the parent drugs when dosed orally in rats and dogs. Dosing unformulated capsules containing the solid prodrugs led to plasma levels equivalent to those observed for dosing formulated solutions of the parent drugs. A direct synthetic process for the preparation of OMP and OEP prodrugs was developed, and the improved synthetic method may be applicable to the preparation of analogous soluble prodrugs of other drug classes with limited solubility.

Characterization of Recombinantly Expressed Rat and Monkey Intestinal Alkaline Phosphatases: In Vitro Studies and In Vivo Correlations

“…Other authors have also reported different dephosphorylation rates depending on the prodrug (Heimbach et al, 2003a;DeGoey et al, 2009). Fosphenytoin has a methylene linker and shows the fastest turnover.…”

“…Clindamycin is a direct prodrug and shows relatively slower turnover. Among the two ritonavir prodrugs, the candidate with a flexible oxymethyl linker cleaves while the direct phosphate shows no turnover, which could be due to the poor accessibility of the phosphate ester into the enzyme active site (DeGoey et al, 2009). The rank order (from slowest to fastest turnover) in rat rIALP was ritonavir oxymethyl phosphate, clindamycin phosphate, dexamethasone phosphate, and fosphenytoin, whereas in RIMS the rank order was clindamycin phosphate, ritonavir oxymethyl phosphate, dexamethasone phosphate, and fosphenytoin.…”

“…Probe phosphate prodrugs, either directly attached to a molecule or incorporated via linkers, were selected for this study. Fosphenytoin (PubChem CID 56339), dexamethasone phosphate (PubChem CID 9400), clindamycin phosphate (PubChem CID 443385), ritonavir oxymethyl phosphate (DeGoey et al, 2009), and ritonavir phosphate (DeGoey et al, 2009) were selected as model prodrugs, which are hydrolyzed to their corresponding highly permeable and poorly soluble parent drugs phenytoin (PubChem CID 657302), dexamethasone (PubChem CID 5743), clindamycin (PubChem CID 29029), and ritonavir (PubChem CID 392622), respectively ( Fig. 1).…”

Accessing the Biocatalytic Potential for C−H‐Activation by Targeted Genome Mining and Screening

“…After the extraction of both, soluble phase and biomass, it could be observed that the highest amount of unconverted substrate remained in the biomass phase (10.4 mg). With a ritonavir solubility of 0.30 mg L −1 in water, precipitation of ritonavir and accumulation in the biomass is likely. The poor solubility makes high substrate loading challenging.…”

Energiedissipation aufgrund von Biegewellen bei Stoßvorgängen gegen dünne Platten

“…Instead, we turned to a synthetic scheme that had previously be used to synthesize OMP prodrugs, namely methylthiomethyl (MTM) ether formation followed by reaction with N‐iodosuccinimide (NIS) and a phosphate 22. 24, 25 We successfully synthesized the desired MTM ether intermediate 9 via a Pummerer rearrangement by stirring 4 in DMSO, acetic anhydride (Ac 2 O), and acetic acid (AcOH) (Scheme ). Unfortunately, treating 9 with NIS and either dibenzyl phosphate or H 3 PO 4 did not lead to any isolable product.…”