Betschart, Claudia, Faller, Michael, Zink, Florence, Hemmig, Rene, Blank, Jutta, Vangrevelinghe, Eric, Bourrel, Marjorie, Glatthar, Ralf, Behnke, Dirk, Barker, Kerstin, Heizmann, Andreas, Angst, Daniela, Nimsgern, Pierre, Jacquier, Sebastien, Junt, Tobias, Collignon Zipfel, Geraldine, Ruzzante, Giulia, Loetscher, Pius, Limonta, Sarah, Hawtin, Stuart, Andre, Cedric Bernard, Boulay, Thomas, Feifel, Roland and Knoepfel, Thomas (2022) Structure-based optimization of a fragment like TLR8 binding screening hit to an in vivo efficacious TLR7/8 antagonist. ACS Medicinal Chemistry Letters. ISSN 1948-58751948-5875

Abstract

Inappropriate activation of TLR7 and TLR8 is linked to several autoimmune diseases, such as e.g. lupus erythematosus. Here we report on the efficient structure-based optimization of the inhibition of TLR8 starting from a co-crystal structure of a small screening hit. Further optimization of the physico-chemical properties for cellular potency and expansion of SAR for dual potency finally resulted in a highly potent TLR7/8 antagonist with demonstrated in vivo efficacy after oral dosing.

Item Type:	Article
Keywords:	Structure-based optimization, TLR7, TLR8, Antagonist
Date Deposited:	06 Apr 2022 00:45
Last Modified:	06 Apr 2022 00:45
URI:	https://oak.novartis.com/id/eprint/46530