molecules of the month

“compound 9” is an investigational prodrug of pibrentasvir (ABT-530), a key component of AbbVie’s marketed HCV combination Mavyret. Pibrentasvir (PIB) is the largest approved oral small molecule since 1983 (MW = 1113, not including the peptide semaglutide at MW = 4113), and came with some solubility issues (aq. sol. pH 7 = <0.0001 mg/mL). The poor solubility of PIB requires a high excipient/drug ratio for suitable absorption, and is the main reason Mavyret is given in a 3-pill, QD regimen. The AbbVie team investigated solubilizing prodrugs of PIB to enable a single pill formulation with bioequivalence to Mavyret, arriving at the significantly more soluble and bioavailable compound 9. Compound 9 is a trimethyl-lock prodrug, which does not depend on esterase activity for…