Orally bioavailable prodrugs of a BCS class 2 molecule, an inhibitor of HIV-1 reverse transcriptase

The N-2 position of pyridazinone 1, a potent HIV-1 NNRTI that has limited aqueous solubility, was derivatized into a series of hydroxymethyl esters and carbonates as well as one phosphate. The derivatives served as prodrugs to effectively deliver 1 to rat plasma upon oral treatment at 50 mpk. Increases of 4.3- to 8.6-fold in 24-hour exposure of 1 (over that of parent) were observed while the prodrugs and the hydroxymethyl adduct 2 were undetectable.

Graphical abstractPyridazinone 1 was derivatized into a series of hydroxymethyl esters, carbonates and one phosphate. These prodrugs were orally dosed to rats and afforded increases of 4.3- to 8.6-fold in 24-hour exposure of 1 (over that of parent) and not detected in blood plasma.Figure optionsDownload full-size imageDownload as PowerPoint slide