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Optimizing a weakly binding fragment into a potent RORγt inverse agonist with efficacy in an in vivo inflammation model

Carcache, David and Vulpetti, Anna and Kallen, Joerg and Mattes, Henri and Orain, David and Stringer, Rowan and Vangrevelinghe, Eric and Wolf, Romain and Kaupmann, Klemens and Ottl, Johannes and Dawson King, Janet and Cooke, Nigel Graham and Hoegenauer, Klemens and Billich, Andreas and Wagner, Juergen and Guntermann, Christine and Hintermann, Samuel (2018) Optimizing a weakly binding fragment into a potent RORγt inverse agonist with efficacy in an in vivo inflammation model. Journal of medicinal chemistry.

Abstract

The transcription factor RORγt is an attractive drug-target due to its role in the differentiation of IL-17 producing Th17 cells that play a critical role in the etiopathology of several autoimmune diseases. Identification of starting points for RORγt inverse agonists with good properties has been a challenge. We report the identification of a fragment hit which was converted into a potent inverse agonist through fragment optimization, growing and merging efforts. Further analysis of the binding mode revealed that inverse agonism was achieved by an unusual mechanism. In contrast to other reported inverse agonists, there is no direct interaction or displacement of helix 12. Nevertheless, compound 9 proved to be efficacious in a delayed-type hypersensitivity (DTH) inflammation model in rats.

Item Type: Article
Date Deposited: 25 Jul 2018 00:45
Last Modified: 25 Jul 2018 00:45
URI: https://oak.novartis.com/id/eprint/34710

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