molecules of the month

GS-9688 (selgantolimod)

pre-systemic oral toll-like receptor 8 agonist

in multiple Ph. II studies for chron. hep. B

from optimization of lit. dual TLR7/8 agonists

J. Med. Chem., Jun. 3, 2020

Gilead Sciences, Foster City, CA

Structure of small molecule agonist Selgantolimod
1 min read

GS-9688 (selgantolimod) is a potent and selective TLR8 agonist sparing related receptor TLR7, and is intended to induce better immune responses in chronic hepatitis B. Since systemic activation of TLR8 was undesirable, selgantolimod was designed to have high first-pass hepatic clearance to induce effective antiviral immunity in the liver but not systemic immunity. Though the molecule is weakly basic, in the low pH (~4-6) environment of the endosomal compartment, the weakly basic heterocycle is protonated, enabling it to make a favorable charged interaction with Asp543 in TLR8. Also interestingly, since the woodchuck hepatitis virus (WHV) is closely related to hepatitis B, a woodchuck model was used for preclinical experiments supporting clinical development.

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