881208-91-9Relevant academic research and scientific papers
Optimizing a Weakly Binding Fragment into a Potent ROR?t Inverse Agonist with Efficacy in an in Vivo Inflammation Model
Carcache, David A.,Vulpetti, Anna,Kallen, Joerg,Mattes, Henri,Orain, David,Stringer, Rowan,Vangrevelinghe, Eric,Wolf, Romain M.,Kaupmann, Klemens,Ottl, Johannes,Dawson, Janet,Cooke, Nigel G.,Hoegenauer, Klemens,Billich, Andreas,Wagner, Juergen,Guntermann, Christine,Hintermann, Samuel
, p. 6724 - 6735 (2018)
The transcription factor ROR?t 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 ROR?t inverse agonists with good properties has been a challenge. We report the identification of a fragment hit and its conversion 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 observed in the crystal structure. Nevertheless, compound 9 proved to be efficacious in a delayed-type hypersensitivity (DTH) inflammation model in rats.
