Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
3 years ago

Identification and Optimization of Pyrrolo[3,2-d]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B

Identification and Optimization of Pyrrolo[3,2-d]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B
Helen Horton, Florence Herschke, Pierre Raboisson, Jin Hong, Dorien Verstappen, Ilham Smyej, Tim H. M. Jonckers, Bertrand Van Schoubroeck, Debbie Wuyts, Eric Arnoult, Mourad Daoubi Khamlichi, Marianne Tuefferd, Jacques Bollekens, Deborah Dhuyvetter, Wendy Mostmans, Tine Thoné, Herman Borghys, Bart Stoops, Gregory Fanning, Dorien De Pooter, Serge Pieters, Ard Teisman, Frederik Pauwels, Vijay Urmaliya, Werner Embrechts, David C. McGowan, Stefaan Last, Annick Scholliers
Pyrrolo[3,2-d]pyrimidines were identified as a new series of potent and selective TLR7 agonists. Compounds were optimized for their activity and selectivity over TLR8. This presents an advantage over recently described scaffolds that have residual TLR8 activity, which may be detrimental to the tolerability of the candidate drug. Oral administration of the lead compound 54 effectively induced a transient interferon stimulated gene (ISG) response in mice and cynomolgus monkeys. We aimed for a high first pass effect, limiting cytokine induction systemically, and demonstrated the potential for the immunotherapy of viral hepatitis.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00365

DOI: 10.1021/acs.jmedchem.7b00365

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