2,4-Diaminoquinazolines as Dual Toll-like Receptor (TLR) 7/8 Modulators for the Treatment of Hepatitis B Virus

A novel
series of 2,4-diaminoquinazolines was identified as potent
dual Toll-like receptor (TLR) 7 and 8 agonists with reduced off-target
activity. The stereochemistry of the amino alcohol was found to influence
the TLR7/8 selectivity with the (R) isomer resulting
in selective TLR8 agonism. Lead optimization toward a dual agonist
afforded (S)-3-((2-amino-8-fluoroquinazolin-4-yl)­amino)­hexanol 31 as a potent analog, being structurally different from previously
described dual agonists (McGowan J. Med. Chem. 2016, 59, 7936). Pharmacokinetic and pharmacodynamic (PK/PD) studies revealed the
desired high first pass profile aimed at limiting systemic cytokine
activation. In vivo pharmacodynamic studies
with lead compound 31 demonstrated production of cytokines
consistent with TLR7/8 activation in mice and cynomolgus monkeys and
ex vivo inhibition of hepatitis B virus (HBV).