molecules of the month

“compound 9”

trimethyl-lock prodrug of HCV NS5A inh.

improved bioavailability in preclinical species

from derivatization of pibrentasvir

J. Med. Chem., Sep. 3, 2020

AbbVie, North Chicago, IL

Structure of compound 9
1 min read

“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…

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