Long-acting cabotegravir (CAB) extends antiretroviral drug (ARV) administration from daily to monthly. However, dosing volumes, injection site reactions, and health care oversight are obstacles towards broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18, and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB, and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics (PK), and biodistribution. PK studies, performed in mice and rhesus macaques, with the lead 18-carbon ester chain NM2CAB, showed plasma CAB levels above the protein-adjusted 90% inhibitory concentration for up to a year. The NM2CAB, compared to NMCAB and NM3CAB, demonstrated prolonged drug release, plasma circulation time and tissue drug concentrations after a single 45 mg/kg intramuscular injection. These prodrug modifications could significantly improve CAB’s effectiveness.

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A practical synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol—a key intermediate in the synthesis of darunavir—from monopotassium isocitrate is described. The isocitric acid salt, obtained from a high-yielding fermentation fed by sunflower oil, was converted in several steps to a tertiary amide. This amide, along with the compound’s ester functionalities, was reduced with lithium aluminum hydride to give, on acidic workup, a transient aminal-triol. This was converted in situ to the title compound, the bicyclic acetal furofuranol side chain of darunavir, a protease inhibitor used in treatment of HIV/AIDS. Key to the success of this process was identifying an optimal amide that allowed for complete reaction and successful product isolation. N-Methyl aniline amide was identified as the most suitable substrate for the reduction and the subsequent cyclization to the desired product. Thus, the side chain is produced in 55% overall yield from monopotassium isocitrate.

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