Knoepfel, Thomas, Nimsgern, Pierre, Jacquier, Sebastien, Bourrel, Marjorie, Vangrevelinghe, Eric, Glatthar, Ralf, Behnke, Dirk, Alper, Phillip, Michellys, Pierre, Deane, Jonathan, Junt, Tobias, Collignon Zipfel, Geraldine, Limonta, Sarah, Hawtin, Stuart, Andre, Cedric Bernard, Boulay, Thomas, Loetscher, Pius, Faller, Michael, Blank, Jutta, Feifel, Roland and Betschart, Claudia (2020) Target-Based Identification and Optimization of 5-Indazol-5-yl Pyridones as Toll-like Receptor 7 and 8 Antagonists using a Biochemical TLR8 Antagonist Competition Assay. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

Abstract

Inappropriate activation of the endosomal TLR7 and TLR8 occurs in several autoimmune diseases, in particular systemic lupus erythematosus (SLE). Herein, the development of a TLR8 antagonist competition assay and its application for hit generation of dual TLR7/8 antagonists are reported. The structure guided optimization of the pyridone hit 3 using this biochemical assay in combination with cellular and TLR8 co-crystal structural data resulted in the identification of a highly potent and selective TLR7/8 antagonist (27) with in vivo efficacy. The two key steps for optimization were (1) a core morph guided by a TLR7 homology model in order to achieve a dual TLR7/8 antagonism profile and (2), introduction of a fluorine in the piperidine ring to reduce its basicity, resulting in attractive oral PK properties and improved TLR8 binding affinity.

Item Type:	Article
Date Deposited:	14 Aug 2020 00:45
Last Modified:	14 Aug 2020 00:45
URI:	https://oak.novartis.com/id/eprint/41810