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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

Knoepfel, Thomas and Nimsgern, Pierre and Jacquier, Sebastien and Bourrel, Marjorie and Vangrevelinghe, Eric and Glatthar, Ralf and Behnke, Dirk and Alper, Phillip and Michellys, Pierre and Deane, Jonathan and Junt, Tobias and Collignon Zipfel, Geraldine and Limonta, Sarah and Hawtin, Stuart and Andre, Cedric Bernard and Boulay, Thomas and Loetscher, Pius and Faller, Michael and Blank, Jutta and 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

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