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

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posted on 02.07.2018, 00:00 by Werner Embrechts, Florence Herschke, Frederik Pauwels, Bart Stoops, Stefaan Last, Serge Pieters, Vineet Pande, Geert Pille, Katie Amssoms, Ilham Smyej, Deborah Dhuyvetter, Annick Scholliers, Wendy Mostmans, Kris Van Dijck, Bertrand Van Schoubroeck, Tine Thone, Dorien De Pooter, Gregory Fanning, Tim H. M. Jonckers, Helen Horton, Pierre Raboisson, David McGowan
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).