1区 · 医学
Article
作者: Embrechts, Werner ; Herschke, Florence ; Pauwels, Frederik ; Stoops, Bart ; Last, Stefaan ; Pieters, Serge ; Pande, Vineet ; Pille, Geert ; Amssoms, Katie ; Smyej, Ilham ; Dhuyvetter, Deborah ; Scholliers, Annick ; Mostmans, Wendy ; Van Dijck, Kris ; Van Schoubroeck, Bertrand ; Thone, Tine ; De Pooter, Dorien ; Fanning, Gregory ; Jonckers, Tim H. M. ; Horton, Helen ; Raboisson, Pierre ; McGowan, David
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).